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

HRID 1437872Notes

Reaction equation

HRID 1437872 reaction equation
C(O[C:6]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.[CH3:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH:23]([C:30](Cl)=[O:31])C2=O.N1C=CC=CC=1.Cl>ClCCCl.O1CCOCC1.C(O)(=O)C>[F:19][C:16]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[C:30](=[O:31])[C:23]2[C@@H:24]3[C:27]([CH3:29])([CH3:28])[C@@:21]([CH3:20])([CH2:26][CH2:25]3)[C:6]=2[NH:8]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 57941306(1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride2×HCID 57941461N'-(2-trifluoromethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 57941458(4s,7r)-2-(2-Trifluoromethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 46.6%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 176Acetic AcidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

N′-(2-Trifluoromethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.85 g, 6.6 mmol) was added in one portion to a ice-bath-cooled solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.09 g, 5.1 mmol) in a mixture of 1,2-dichloroethane (12 mL) and pyridine (0.6 mL, 7.6 mmol). The mixture was diluted with 1,2-dichloroethane (6 mL) to facilitate stirring. The reaction mixture was heated at 50° C. for 1 h, then cooled to room temperature. A 4 M solution of HCl in dioxane (3.6 mL) was added via the condenser and the solution was stirred for several minutes. Glacial acetic acid (7 mL) was added and the reaction mixture was heated in an oil bath at ˜100° C. for 2 h. The reaction mixture was stirred overnight at room temperature and then evaporated. Dichloromethane was added and the solution was washed twice with brine. The aqueous washes were back-extracted with dichloromethane, and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 120 g column, eluting with 0-40% ethyl acetate/hexanes to give (4S,7R)-2-(2-trifluoromethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (0.80 g, 46%) as a light brown solid.

Workup

  1. temperaturecooled to room temperature
  2. stirringthe solution was stirred for several minutes
  3. temperaturethe reaction mixture was heated in an oil bath at ˜100° C. for 2 h
  4. stirringThe reaction mixture was stirred overnight at room temperature
  5. customevaporated
  6. additionDichloromethane was added
  7. washthe solution was washed twice with brine
  8. extractionThe aqueous washes were back-extracted with dichloromethane
  9. washthe combined organic layers were washed with brine
  10. dry with materialdried (magnesium sulfate)
  11. filtrationfiltered
  12. customevaporated
  13. custompurified
  14. washeluting with 0-40% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-7b995afe73534d18bdee63bc01585ef3
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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