Hydrochloric Acid → HCID 57941465, compound

HRID 1438057Notes

Reaction equation

HRID 1438057 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]([C:38]#[N:39])[CH:35]=[CH:34][C:33]=1[F:40])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[F:40][C:33]1[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[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

7

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 69017429HCID 69017429, compound

Product 1

HCID 57941465HCID 57941465, compoundYield 10%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Conditions

Temperature
50 °C

Procedure

Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.00 g, 4.7 mmol) of in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(5-cyano-2-fluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (700 mg, 2.6 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 triturated with ether and then petroleum ether and the solvent was removed. The residue was co-evaporated with methanol and the petroleum ether and then further purified on an ISCO system, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol, diethyl ether, and petroleum ether, and then dried under high vacuum at room temperature to give 4-fluoro-3-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzonitrile (84 mg, 10%) as a white foam. APCI(+)-MS (M+H) 326.

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. customThis was triturated with ether
  9. custompetroleum ether and the solvent was removed
  10. customthe petroleum ether and then further purified on an ISCO system
  11. washeluting with 50-100% ethyl acetate/hexanes
  12. customFractions homogeneous for the product were evaporated, co-evaporated successively with methanol, diethyl ether, and petroleum ether
  13. customdried under high vacuum at room temperature

Sources & evidence

ORD record
ord-596f1b2cdecb4b64be2a845950c48724
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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