Dichloromethane → (4s,7r)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1-(3,3,3-trifluoro-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1438004Notes

Reaction equation

HRID 1438004 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.Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].[I-].ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[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[N:10]1[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 30165Iodide IonHCID 27251143-Bromo-1,1,1-trifluoropropaneHCID 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 57941511(4s,7r)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1-(3,3,3-trifluoro-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 17.4%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 200 mg, 0.66 mmol), tetrabutylammonium iodide (190 mg, 0.51 mmol) and 3-bromo-1,1,1-trifluoropropane (Aldrich; 5.00 g, 28.25 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 4 days. An additional portion of tetrabutylammoiun iodide (190 mg, 0.51 mmol) was added and the reaction mixture was heated at 100° C. for 3 days and then cooled to room temperature. Dichloromethane (150 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 30-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was triturated with petroleum ether. The mixture was evaporated again and dried at 70° C. under high vacuum to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3,3,3-trifluoro-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (46 mg, 17%) as a light yellow solid. ES(+)-MS (M+H) 401.

Workup

  1. temperaturethe reaction mixture was heated at 100° C. for 3 days
  2. temperaturecooled to room temperature
  3. washthe solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL)
  4. dry with materialdried (magnesium sulfate)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified
  8. washeluting with 30-100% ethyl acetate/hexanes
  9. customFractions homogeneous for the product were evaporated
  10. customthe residue was triturated with petroleum ether
  11. customThe mixture was evaporated again
  12. customdried at 70° C. under high vacuum

Sources & evidence

ORD record
ord-3a0e922d6aa744a4b2d906430ef5f08f
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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