Hydrochloric Acid → (1R,7S)-4-(2,5-dichlorophenyl)-1,3,10,10-tetramethyl-3,4-diazatricyclo[5.2.1.02,6]dec-2(6)-en-5-one

HRID 1438052Notes

Reaction equation

HRID 1438052 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]([NH:29][N:30]([C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[Cl:39])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[Cl:39][C:33]1[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=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 chloride2×HCID 69018639n'-(2,5-Dichloro-phenyl)-n'-methyl-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 16116998(1R,7S)-4-(2,5-dichlorophenyl)-1,3,10,10-tetramethyl-3,4-diazatricyclo[5.2.1.02,6]dec-2(6)-en-5-oneYield 44.1%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Triethylamine (1.2 mL, 8.6 mmol) was added dropwise 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; 880 mg, 4.1 mmol) in 1,2-dichloroethane (8 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,5-dichloro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (751 mg, 2.58 mmol) in 1,2-dichloroethane (14 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 30 min. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated at reflux for 1 h and then allowed to cool to room temperature. Dichloromethane (150 mL) was added and the mixture was washed with 1:1 water/brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 120 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated successively with methanol and diethyl ether. The residue was dried overnight under high vacuum at 70° C. to give (4S,7R)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (400 mg, 44%) as a white solid. ES(+)-MS (M+H) 351.

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. temperaturethe mixture was heated
  4. temperatureat reflux for 1 h
  5. washthe mixture was washed with 1:1 water/brine (30 mL)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. customevaporated
  9. custompurified
  10. washeluting with 20-100% ethyl acetate/hexanes
  11. customFractions homogeneous for the product were evaporated
  12. customThe residue was dried overnight under high vacuum at 70° C.

Sources & evidence

ORD record
ord-536b0d6548af483a813d2a52064032fb
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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