Dimethyl Sulfate → (4s,7r)-2-(2,4-Difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1437927Notes

Reaction equation

HRID 1437927 reaction equation
S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1>[OH-].[Na+]>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[N:17]1[CH3:5]

Participants

4

Reactant 2

HCID 6497Dimethyl Sulfate2×HCID 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 57941500(4s,7r)-2-(2,4-Difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 11%

Reagents, catalysts & solvents 1

HCID 14798Sodium HydroxideSolvent2×

Procedure

A mixture of dimethyl sulfate (0.56 mL, 5.9 mmol) and (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; 1.82 g, 6.0 mmol) in 1 M NaOH (25 mL) was heated at 45 degrees for 4.5 h, then a further portion of dimethyl sulfate (0.56 mL, 5.9 mmol) was added and the reaction was heated at 45 degrees overnight. NaOH was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were evaporated and purified by column chromatography, eluting with 10-50% ethyl acetate/dichloromethane followed by recrystallization from ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (199 mg, 11%) as a white solid. ES(+)-MS (M+H) 319.

Workup

  1. temperaturewas heated at 45 degrees for 4.5 h
  2. temperaturethe reaction was heated at 45 degrees overnight
  3. extractionthe mixture was extracted twice with ethyl acetate
  4. customThe combined organic layers were evaporated
  5. custompurified by column chromatography
  6. washeluting with 10-50% ethyl acetate/dichloromethane
  7. customfollowed by recrystallization from ethyl acetate/hexanes

Sources & evidence

ORD record
ord-1381b80eb01344e4b7c0ebcbdda940ea
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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