3-((1-Methylpiperidin-4-yl)oxy)aniline → HCID 117996730, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-(1-methylpiperidin-4-yloxy)aniline (36.5 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 µmol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 µmol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)/IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (100 mL), The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH/7MNH3 in EtOAc. lcms still showed 30% unreacted aniline. Fractions evaporated.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5µ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(1-methylpiperidin-4-yloxy)phenylamino)nicotinamide (23.00 mg, 32.8 %) as a cream solid.

Provenance & Evidence