3-Bromo-5-fluorobenzonitrile → 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide

Participants

Reaction Conditions

Reaction Steps

To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (300 mg, 0.87 mmol), cesium carbonate (1104 mg, 3.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (126 mg, 0.22 mmol) and 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) in degassed 1,4-dioxane (2ml), was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (59.7 mg, 0.07 mmol). The suspension was heated in a sealed container up to 85-95°C for 16hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the product which still containing some impurities (see UPLC 03441-77-003). The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (330 mg, 82 %) as a clear white solid.

Provenance & Evidence