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

HRID 1438059Notes

Reaction equation

HRID 1438059 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]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[F:41])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[F:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:40])([F:39])[F:38])=[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 chlorideHCID 57941369N'-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 57941449(4s,7r)-2-(2-Fluoro-5-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 31.3%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

Triethylamine (518 μL, 3.7 mmol) was added dropwise to a cooled (0° C.) solution (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (418 mg, 1.95 mmol) of in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (380 mg, 1.23 mmol) in 1,2-dichloroethane (6 mL) was added over 2 min. 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 2 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with ether and then petroleum ether. The residue was triturated with hexanes, and the solid was dried under high vacuum at 70° C. overnight and then at 85° C. for 1 h to give (4S,7R)-2-(2-fluoro-5-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (142 mg, 30%) as a light yellow solid. ES(+)-MS (M+H) 369.

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 2 h
  3. temperatureto cool to room temperature
  4. washthe mixture was washed with 1:1 water/brine (20 mL)
  5. dry with materialdried (magnesium sulfate)
  6. filtrationfiltered
  7. customevaporated
  8. custompurified
  9. washeluting with 20-50% ethyl acetate/hexanes
  10. customFractions homogeneous for the product were evaporated
  11. customThe residue was triturated with hexanes
  12. customthe solid was dried under high vacuum at 70° C. overnight

Sources & evidence

ORD record
ord-85f41cbe65294b1f980324fe998f6e0f
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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