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

HRID 1437973Notes

Reaction equation

HRID 1437973 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]([CH:37]1[CH2:39][CH2:38]1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH:37]1([N:29]2[C:10]3[C@@:9]4([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]4)[C:11]=3[C:18](=[O:19])[N:30]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:39][CH2:38]1

Participants

7

Reactant 5

HCID 313Hydrochloric Acid2×HCID 8471TriethylamineHCID 312751,4-Dioxane2×HCID 57941306(1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride2×HCID 57941480N-cyclopropyl-N'-phenyl-hydrazinecarboxylic acid tert-butyl ester

Product 1

HCID 57941489(4s,7r)-1-Cyclopropyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 43%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Triethylamine (120 μL, 0.86 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; 90 mg, 0.42 mmol) in 1,2-dichloroethane (1 mL) over 1 min. A solution of N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (66 mg, 0.27 mmol) in 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 90 min. The reaction mixture was cooled. 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. A further portion of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the mixture was heated in an oil bath at 100° C. for 2 h. The solvent was evaporated. Dichloromethane (30 mL) was added and the mixture was washed with 1:1 water/brine (10 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with dichloromethane and then petroleum ether. The residue was dried under high vacuum at 75° C. overnight to give (4S,7R)-1-cyclopropyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (35 mg, 43%) as a light yellow solid. APCI(+)-MS (M+H) 309.

Workup

  1. waitin an oil bath at 50° C. for 90 min
  2. temperatureThe reaction mixture was cooled
  3. temperaturethe mixture was heated in an oil bath at 100° C. for 1 h
  4. temperaturethe mixture was heated in an oil bath at 100° C. for 2 h
  5. customThe solvent was evaporated
  6. additionDichloromethane (30 mL) was added
  7. washthe mixture was washed with 1:1 water/brine (10 mL)
  8. dry with materialdried (magnesium sulfate)
  9. filtrationfiltered
  10. customevaporated
  11. custompurified
  12. washeluting with 25-100% ethyl acetate/hexanes
  13. customFractions homogeneous for the product were evaporated
  14. customThe residue was dried under high vacuum at 75° C. overnight

Sources & evidence

ORD record
ord-eb755e030bef43a1b19b1a650bf32e9e
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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