Potassium Phosphate, Tribasic → 5,7-difluoro-N-(2'-methoxy-5-morpholino-2,4'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Participants

Reaction Conditions

Reaction Steps

N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (42.8 mg, 0.091 mmol), 2-methoxypyridin-4-ylboronic acid (28.7 mg, 0.19 mmol), tricyclohexylphosphine (5.1 mg, 0.018 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5.7 mg, 6.2 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 mL) and aq. 1.3M potassium phosphate tribasic (0.22 mL, 0.29 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-100% EtOAc in hexanes) to afford an impure yellow residue. The light yellow film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (1H, dt, J=4.8, 1.4 Hz), 8.35 (1H, m), 8.10 (1H, m), 7.98 (2H, m), 7.70 (1H, m), 7.47 (1H, m), 7.37 (1H, m), 7.21 (1H, s), 7.00 (2H, ddd, J=13.5, 8.6, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 4.05 (3H, m), 3.89 (4H, m), 3.28 (4H, m), 2.31 (3H, m). Mass Spectrum (pos.) m/e: 541.2 (M+1).

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