Hydrochloric Acid → 3-(4'-Chloro-3'-fluoro-4-methylbiphenyl-3-yl)-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

HRID 1466457Notes

Reaction equation

HRID 1466457 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]2[C:9](=[O:19])[NH:10][C:11]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.S([O-])([O-])(=O)=O.[Mg+2]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]3[C:9](=[O:19])[NH:10][C:11]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[C:12]=3[OH:13])[CH:7]=2)=[CH:24][C:23]=1[F:31]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 24083Sulfuric acid magnesium salt (1:1)HCID 27786564-Chloro-3-fluorophenylboronic AcidHCID 673745843-(5-Bromo-2-methylphenyl)-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

Product 1

HCID 682833003-(4'-Chloro-3'-fluoro-4-methylbiphenyl-3-yl)-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

Under argon, 36.4 mg (0.05 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium complex were added to 150 mg (0.45 mmol) of the compound from Example 13A in 15 ml of degassed 1,2-dimethoxyethane. The mixture was stirred at room temperature for 5 minutes, and 117 mg (0.67 mmol) of (4-chloro-3-fluorophenyl)boronic acid and a solution of 509 mg (1.56 mmol) of caesium carbonate in 0.9 ml of degassed water was then added. Under microwave irradiation, the reaction mixture was heated at 150° C. for 10 minutes. After cooling, 0.3 ml of concentrated aqueous hydrogen chloride solution were added, magnesium sulphate was added, the mixture was filtered through silica gel, the filter cake was washed with ethyl acetate and the mixture was concentrated. Purification of the crude product by HPLC chromatography (C18 phase, mobile phase: water/acetonitrile gradient/0.1% formic acid) gave 43.7 mg (25% of theory) of the title compound.

Workup

  1. customUnder microwave irradiation
  2. temperaturethe reaction mixture was heated at 150° C. for 10 minutes
  3. temperatureAfter cooling
  4. filtrationthe mixture was filtered through silica gel
  5. washthe filter cake was washed with ethyl acetate
  6. concentrationthe mixture was concentrated
  7. customPurification of the crude product by HPLC chromatography (C18 phase, mobile phase

Sources & evidence

ORD record
ord-9a89354050e342e2896bced50c23ea97
Source dataset
uspto-grants-2015_04
Patent number
US09000026B2

Reaction notes

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