Hydrochloric Acid → 3-(4'-Chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diazaspiro[4.5]dec-3-en-2-one

HRID 1022389Notes

Reaction equation

HRID 1022389 reaction equation
Br[C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[C:9](=[O:21])[NH:10][C:11]4([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]4)[C:12]=3[OH:13])[CH:7]=2)=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 742994-Chlorophenylboronic acidHCID 596145973-(5-Bromo-4-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diazaspiro[4.5]dec-3-en-2-one

Product 1

HCID 596145833-(4'-Chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diazaspiro[4.5]dec-3-en-2-one

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a suspension of 3-(5-bromo-4-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (230 mg) in dimethoxyethane (10 ml) under nitrogen atmosphere is added tetrakis(triphenylphosphine)palladium(0) (35 mg) and the mixture stirred at room temperature for 15 minutes. After further addition of water (2 ml), 4-chlorophenylboronic acid (112 mg) and sodium carbonate (250 mg), the mixture is heated at reflux for 8 hours. The reaction mixture is acidified at room temperature with 1N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 5:1). Yield: 170 mg of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C24) as a solid.

Workup

  1. temperaturethe mixture is heated
  2. temperatureat reflux for 8 hours
  3. extractionextracted with ethyl acetate (3×)
  4. washThe combined organic layers are washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customThe residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 5:1)

Sources & evidence

ORD record
ord-38f47f3b1dd04257b9bba3db25a9f909
Source dataset
uspto-grants-2014_05
Patent number
US08722578B2

Reaction notes

Loading…