Lithium Hydroxide → 5-tert-Butyl-2-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)isoindolin-1-one

Participants

Reaction Conditions

Reaction Steps

A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 103f (556 mg, 1.20 mmol), 105a (300 mg, 1.00 mmol), sodium carbonate (424 mg, 4.00 mmol), water (4 mL) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 20 min, tetrakis(triphenylphosphine)-palladium(0) (115 mg, 0.100 mmol) was added, and the reaction mixture was heated at 100° C. for 4 h. After this time, the reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with a 1:10 mixture of methanol and methylene chloride (30 mL). The filtrate was concentrated under reduced pressure to afford a brown residue. Another 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with residue obtained above, THF (5 mL), ethanol (5 mL), water (5 mL) and lithium hydroxide (86.4 mg, 3.60 mmol). The mixture was stirred at 50° C. for 2 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 35% (190 mg) yield of 105 as a white solid: mp 225-227° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 2H), 7.72 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.22 (s, 1H), 5.88 (s, 1H), 4.89 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.35 (d, 2H, J=4.5 Hz), 3.57 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 512.3 (M+H).

Provenance & Evidence