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

HRID 1437965Notes

Reaction equation

HRID 1437965 reaction equation
Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:22](=[O:23])[C:21]2[C@@H:20]3[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]3)[C:16]=2[NH:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH:5]1([CH2:4][N:15]2[C:16]3[C@@:17]4([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:20]([CH2:19][CH2:18]4)[C:21]=3[C:22](=[O:23])[N:14]2[C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[CH2:3][CH2:2]1

Participants

6

Reactant 2

HCID 81503BromomethylcyclopropaneHCID 57941339(4s,7r)-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 57941508(4s,7r)-1-(Cyclopropyl)methyl-7,8,8-trimethyl-2-(2,4-difluoro-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 43%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (bromomethyl)cyclopropane (2 mL, 20.6 mmol), (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 14; 414 mg, 1.36 mmol) and tetra-n-butylammonium iodide (0.80 g, 2.2 mmol) in N,N-dimethylformamide (5 mL) was heated in a sealed tube in an oil-bath at 100° C. for 20 h. The reaction mixture was cooled to room temperature and then diluted with dichloromethane (200 mL). The solution was washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL), then dried (magnesium sulfate), filtered, and evaporated, and the residue was purified on an Isco 120 g column, eluting with 30-100% ethyl acetate/hexanes to give (4S,7R)-1-(cyclopropyl)methyl-7,8,8-trimethyl-2-(2,4-difluoro-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (209 mg, 43%) as an pale yellow gum. APCI-MS (M+H) 359.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washThe solution was washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL)
  3. dry with materialdried (magnesium sulfate)
  4. filtrationfiltered
  5. customevaporated
  6. customthe residue was purified on an Isco 120 g column
  7. washeluting with 30-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-162194783ffa46808c0918ff4f3c3283
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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