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

HRID 1438066Notes

Reaction equation

HRID 1438066 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]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[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]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[CH3:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 57941380HCID 57941380, compound2×HCID 57941521N-benzyl-N'-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 16117000(4r,7s)-1-Benzyl-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 11%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

Triethylamine (440 μL, 3.2 mmol) was added to solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 329 mg, 1.5 mmol) in 1,2-dichloroethane (6 mL) over 1 min. Then a solution of N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 1.38 mmol) in 1,2-dichloroethane (12 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 50° C. for 2 h and then at 60° C. for 1 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. The reaction mixture was allowed to cool, silica gel was added, the solvent was evaporated and the mixture was purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes and then 5% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, and then treated with methanol and charcoal. This mixture was stirred for 20 min, filtered through Celite and evaporated to give an orange gum. The gum was purified for a second time using an ISCO 40 g column, eluting with 2-4% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at room temperature to give (4R,7S)-1-benzyl-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (57 mg, 11%) as an off-white foam. ES(+)-MS (M+H) 387.

Workup

  1. temperatureheated in an oil bath at 50° C. for 2 h
  2. waitat 60° C. for 1 h
  3. temperaturethe mixture was heated in an oil-bath at 100° C. for 1 h
  4. temperatureto cool
  5. additionsilica gel was added
  6. customthe solvent was evaporated
  7. customthe mixture was purified
  8. washeluting with 60-100% ethyl acetate/hexanes
  9. customFractions homogeneous for the product were evaporated
  10. additiontreated with methanol and charcoal
  11. stirringThis mixture was stirred for 20 min
  12. filtrationfiltered through Celite
  13. customevaporated
  14. customto give an orange gum
  15. customThe gum was purified for a second time
  16. washeluting with 2-4% methanol/dichloromethane
  17. customFractions homogeneous for the product were evaporated
  18. customdried under high vacuum at room temperature

Sources & evidence

ORD record
ord-eca1076671de4e7fb24b9f4e38fc537c
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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