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

HRID 1438055Notes

Reaction equation

HRID 1438055 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(OC([N:29]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH2:39]([N:29]1[C:10]2[C@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 8471TriethylamineHCID 312751,4-Dioxane2×HCID 57941380HCID 57941380, compound2×HCID 57941512N-benzyl-N'-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 16116999(4r,7s)-1-Benzyl-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 3.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Triethylamine (380 μL, 2.7 mmol) was added dropwise to a solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 318 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N-benzyl-N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (265 mg, 0.72 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 100° C. for 45 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. An additional portion of HCl in dioxane (4 M; 2 mL, 8 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 2 h. The reaction mixture was allowed to cool to room temperature and dichloromethane (100 mL) was added. The mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified on an ISCO system using a 12 g column, eluting with 33-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at 90° C. to give (4R,7S)-1-benzyl-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (10 mg, 3%) as a pale yellow solid. ES(+)-MS (M+H) 427.

Workup

  1. temperatureheated in an oil bath at 100° C. for 45 min
  2. temperaturethe mixture was heated in an oil-bath at 100° C. for 1 h
  3. temperaturethe mixture was heated in an oil-bath at 100° C. for 2 h
  4. temperatureto cool to room temperature
  5. washThe mixture was washed with 1:1 water/brine (20 mL)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. customevaporated
  9. custompurified on an ISCO system
  10. washeluting with 33-100% ethyl acetate/hexanes
  11. customFractions homogeneous for the product were evaporated
  12. customdried under high vacuum at 90° C.

Sources & evidence

ORD record
ord-06a6700bfc81444184a529ad31f5ce25
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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