Ethyl Acetate → 6-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

HRID 50718

Reaction equation

HRID 50718 reaction equation
Br[C:2]1[CH2:3][CH:4]2[C:9]([CH3:11])([CH3:10])[O:8][C:7](=[O:12])[NH:6][C:5]2=[C:13]([F:15])[CH:14]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:26][C:18]1[CH:19]=[C:20]([C:2]2[CH:14]=[C:13]([F:15])[C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:22][C:17]=1[F:16]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 27346603-Chloro-4-fluorophenylboronic Acid (contains varying amounts of Anhydride)HCID 688225046-Bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one

Product 1

HCID 98584066-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneYield 66%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0.176 g, 0.64 mmol), 4-fluoro-3-chlorophenyl boronic acid (0.15 g, 0.84 mmol), tetrakis(triphenylphosphine)-palladium (0) (0.04 g, 0.032 mmol), and sodium carbonate (0.20 g, 1.92 mmol) in DME (10 mL) and water (5 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 6-(3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (0.13 g, 66%): mp 246-248° C.; 1H-NMR (DMSO-d6) δ10.5 (s, 1H), 8.00 (dd, 1H, J=7.09, 2.32 Hz), 7.78-7.73 (m, 1H), 7.62 (dd, 1H, J=11.86, 1.77 Hz), 7.7 (t, 2H, J=9 Hz), 1.7 (s, 6H); MS (APCI) m/z 324 ([M+H]+, 100%); Anal. Calc. For C16H12F2NO2.0.5 H2O: C, 57.76; H, 3.94; N, 4.21. Found: C, 57.49; H, 3.69; N, 4.03.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washThe organic layer was washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL)
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-e8bb3f5438894f7299b4562676c75359
Source dataset
uspto-grants-2004_03
Patent number
US06713478B2

Linked notes

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