Hydrochloric Acid → 3-(3',4'-Difluoro-4-methylbiphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

HRID 1466463Notes

Reaction equation

HRID 1466463 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].Cl>COCCOC>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[C:9](=[O:21])[NH:10][C:11]4([CH2:14][CH2:15][C:16]([F:20])([F:19])[CH2:17][CH2:18]4)[C:12]=3[OH:13])[CH:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 27343373,4-Difluorobenzeneboronic acidHCID 682831323-(5-Bromo-2-methylphenyl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

Product 1

HCID 601683323-(3',4'-Difluoro-4-methylbiphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Procedure

0.74 g (2.0 mmol) of the compound from Example 11A was initially charged in 5 ml of ethylene glycol dimethyl ether, 14.5 ml of 2M aqueous sodium carbonate solution were added dropwise and 10 mg of bis(trisphenylphosphine)palladium(II) chloride were added. 0.35 g (2.2 mmol) of 3,4-difluorophenylboronic acid was then added, and the mixture was stirred under reflux overnight. After cooling, the mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate, and the extract was dried and concentrated. Purification was carried out by MPLC separation on silica gel using the mobile phase hexane/ethyl acetate 1/1. This gave 0.7 g (70% of theory) of the title compound. 395 mg were then purified again by HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm; mobile phase: water/acetonitrile gradient with addition of 0.1% formic acid]. This gave 121 mg of the title compound.

Workup

  1. temperatureunder reflux overnight
  2. temperatureAfter cooling
  3. extractionextracted with ethyl acetate
  4. customthe extract was dried
  5. concentrationconcentrated
  6. customPurification
  7. customwas carried out by MPLC separation on silica gel using the mobile phase hexane/ethyl acetate 1/1
  8. custom395 mg were then purified again by HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm; mobile phase: water/acetonitrile gradient with addition of 0.1% formic acid]

Sources & evidence

ORD record
ord-ce231a52315b4f9b84e36b47d8687de2
Source dataset
uspto-grants-2015_04
Patent number
US09000026B2

Reaction notes

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