Ammonium Chloride → 3-(2-fluorophenyl)-3-hydroxy-5-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

HRID 490144

Reaction equation

HRID 490144 reaction equation
C([Li])(CC)C.C(O[C:11](=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(C)(C)C.C(OC(=O)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])=[O:29])C.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1.CCCCCC.C1CCCCC1>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1([OH:29])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:15]=2)[NH:12][C:11]1=[O:23]

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 112307451,1-Dimethylethyl N-[4-(trifluoromethyl)phenyl]carbamateHCID 21644544Ethyl 2-(2-fluorophenyl)-2-oxoacetateHCID 178418400CID 53628100

Product 1

HCID 231206953-(2-fluorophenyl)-3-hydroxy-5-(trifluoromethyl)-1,3-dihydro-2H-indol-2-oneYield 16.3%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 22494920Cyclohexane hexaneSolvent

Conditions

Temperature
-40 °C

Procedure

16.8 mL of a hexane-cyclohexane solution of 1.0 mol/L sec-butyllithium was added dropwise under −78° C. cooling to a 15 mL tetrahydrofuran solution of 2 g of tert-butyl[4-(trifluoromethyl)phenyl]carbamate, and the reaction mixture was stirred for 1 hour. The temperature was then raised to −40° C., and the reaction mixture was stirred for 2.5 hours at that temperature. The reaction mixture was cooled back down to −78° C., a 7.5 mL tetrahydrofuran solution of 2.23 g of ethyl(2-fluorophenyl)(oxo)acetate was added dropwise, and the reaction mixture was stirred for 2 hours at the same temperature. The temperature was then raised to room temperature, and the reaction mixture was stirred for 12 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/1; v/v) to obtain 389 mg of the titled compound (colorless powder).

Workup

  1. stirringthe reaction mixture was stirred for 2.5 hours at that temperature
  2. temperatureThe reaction mixture was cooled back down to −78° C.
  3. stirringthe reaction mixture was stirred for 2 hours at the same temperature
  4. temperatureThe temperature was then raised to room temperature
  5. stirringthe reaction mixture was stirred for 12 hours
  6. washthe organic layer was washed with saturated brine
  7. dry with materialdried with magnesium sulfate
  8. distillationthe solvent was distilled off under reduced pressure
  9. customThe residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/1; v/v)

Sources & evidence

ORD record
ord-39d2f4d5b355497d89243307d32f3284
Source dataset
uspto-grants-2009_05
Patent number
US07528124B2

Linked notes

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