Hydrochloric Acid → (4s,7r)-2-(2,4-Bis-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1438068Notes

Reaction equation

HRID 1438068 reaction equation
C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1[C:41]([F:44])([F:43])[F:42])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.O>[F:42][C:41]([F:43])([F:44])[C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 57941306(1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride4×HCID 57941374N'-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 57941343(4s,7r)-2-(2,4-Bis-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 66.5%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent3×HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

Triethylamine (840 μL, 6.0 mmol) was added to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 612 mg, 2.9 mmol) in 1,2-dichloroethane (8 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 1.8 mmol) in 1,2-dichloroethane (14 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 30 min. An additional portion of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 0.6 g, 2.8 mmol) in 1,2-dichloroethane (6 mL) was added and the mixture was heated at 50° C. for 45 min. The reaction mixture was allowed to cool. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the reaction mixture was heated at reflux for 1 h, allowed to cool, poured into water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (magnesium sulfate), filtered, evaporated, and chromatographed, eluting with 40% ethyl acetate/hexanes) to give (4S,7R)-2-(2,4-bis-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (501 mg, 66%) as an off-white solid. APCI(+)-MS (M+H) 419.

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min
  2. waitin an oil bath at 50° C. for 30 min
  3. temperatureto cool
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 1 h
  6. temperatureto cool
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. dry with materialThe combined organic layers were dried (magnesium sulfate)
  9. filtrationfiltered
  10. customevaporated
  11. customchromatographed
  12. washeluting with 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-daf0982b425c41a7a1ad9fe12f35c2eb
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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