Hydrochloric Acid → HCID 57941305, compound

HRID 1438032Notes

Reaction equation

HRID 1438032 reaction equation
C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[N:16]1[C:36](=[O:37])[C:29]2[C@@H:30]3[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]3)[C:28]=2[N:15]1[CH3:13]

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 69017421HCID 69017421, compound

Product 1

HCID 57941305HCID 57941305, compoundYield 27.5%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(2,5-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (305 mg, 1.2 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.7 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated 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; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to give a yellow foam. This was taken up in ethyl acetate and washed with water. The organic layer was evaporated and the residue was further purified on an ISCO system, eluting with 50-90% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol, and diethyl ether, and then dried under high vacuum at 75° C. overnight to give (4S,7R)-2-(2,5-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (105 mg, 27%) as a white solid. ES(+)-MS (M+H) 319.

Workup

  1. temperatureto cool
  2. temperaturethe mixture was heated
  3. temperatureat reflux for 1.5 h
  4. temperatureto cool to room temperature
  5. customThe solvent was evaporated
  6. customthe residue was purified by preparative HPLC
  7. customto give a yellow foam
  8. washwashed with water
  9. customThe organic layer was evaporated
  10. customthe residue was further purified on an ISCO system
  11. washeluting with 50-90% ethyl acetate/hexanes
  12. customFractions homogeneous for the product were evaporated, co-evaporated successively with methanol, and diethyl ether
  13. customdried under high vacuum at 75° C. overnight

Sources & evidence

ORD record
ord-cf1be0b0d10246189218e76daf06576f
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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