Sodium Carbonate → 2-Cyclopropyl-5-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-4H-thieno[3,2-c]pyrrol-6(5H)-one

Participants

Reaction Steps

A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116h (124 mg, 0.300 mmol), 116a (100 mg, 0.300 mmol), sodium carbonate (95 mg, 0.900 mmol), DMF (2.5 mL), water (1.2 mL) and 1,4-dioxane (4 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.003 mmol) was added, and the reaction mixture was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature, and methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (42 mg, 1.00 mmol) were added. The mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 22% yield (32 mg) of 116 as an off-white solid: mp 140-141° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.70 (d, 1H, J=1.1 Hz), 8.64 (s, 1H), 8.29 (d, 1H, J=5.8 Hz), 7.52 (d, 1H, J=2.5 Hz), 7.48 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.31 (dd, 1H, J=5.9, 1.1 Hz), 7.04 (s, 1H), 4.91 (t, 1H, J=5.0 Hz), 4.83 (s, 2H), 4.34 (d, 2H, J=5.0 Hz), 3.60 (s, 3H), 2.29 (m, 1H), 1.12 (m, 2H), 0.82 (m, 2H); MS (ESI+) m/z 486.2 (M+H).

Provenance & Evidence