Sodium Carbonate → Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate

Participants

Reaction Conditions

Reaction Steps

A mixture of methyl 3-amino-2,6-dibromoisonicotinate (11.4 g, 36.6 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (8.7 g, 33.3 mmol), and powdered sodium carbonate (8.12 g, 77 mmol) in a mixture of toluene (90 mL) and methanol (30 mL) was degassed and then backfilled with nitrogen twice. Tetrakis(triphenylphosphine)-palladium(0) (1.93 g, 1.67 mmol) was added and the reaction was degassed and backfilled with nitrogen. After stirred in a 110° C. oil bath for 64 hr, the reaction was cooled and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, and then dried over sodium sulfate and the solvents removed. The residue was suspended in EtOAc and the solid was collected by filtration and washed with EtOAc to give methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)-isonicotinate (3.29 gm, 24%). Flash silica gel chromatography of the filtrate (step gradient elution with hexane containing 10 to 20% EtOAc and then methylene chloride containing 1 to 4% MeOH) gave additional 4.63 g (33%) of pure product and 2.2 g of material that contained 65% of the product according to LC/MS. MS (ESI) m/z 418 and 420 (M−H). 1H NMR (CDCl3) δ ppm 7.83 (1H, s), 7.68 (2H, d, J=8.24 Hz), 7.52 (2H, d, J=7.93 Hz), 5.93 (2H, br. s.), 3.92 (3H, s), 3.78 (4H, br. s.), 3.62 (2H, br. s.), 3.46 (2H, br. s.).

Provenance & Evidence