Hydrochloric Acid → HCID 57941365, compound

HRID 1438034Notes

Reaction equation

HRID 1438034 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]([C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])[NH:30][CH3:31])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[N:29]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:30]1[CH3:31]

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 69017425HCID 69017425, compound

Product 1

HCID 57941365HCID 57941365, compoundYield 47%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Triethylamine (300 μL, 2.15 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; 220 mg, 1.03 mmol) in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N-(2,6-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (167 mg, 0.65 mmol) in 1,2-dichloroethane (6 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 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 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-(2,6-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (97 mg, 47%) as an off-white solid. ES(+)-MS (M+H) 319.

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 1 h
  3. temperatureto cool
  4. temperaturethe mixture was heated
  5. temperatureat reflux for 1.5 h
  6. washthe mixture was washed with 1:1 water/brine (20 mL)
  7. dry with materialdried (magnesium sulfate)
  8. filtrationfiltered
  9. customevaporated
  10. custompurified
  11. washeluting with 20-100% ethyl acetate/hexanes
  12. customFractions homogeneous for the product were evaporated
  13. customThe residue was dried overnight under high vacuum at 70° C.

Sources & evidence

ORD record
ord-4657e1aedfaf4de68edf9d31d5827768
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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