Cesium carbonate → Methyl 3'-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylate

Participants

Reaction Conditions

Reaction Steps

Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed [5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methanol (130 g, 560 mmol, 1.00 equiv), [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (87.5 g, 0.5 equiv), Pd(PPh3)4 (32.3, 28 mmol, 0.05 equiv), Cs2CO3 (365.1 g, 2.00 equiv), water (300 mL), 1,4-dioxane (1200 mL). The resulting solution was stirred for 5 hour at 100° C., then added 2nd batch of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (50 g, 0.3 equiv). The last batch (37 g, 0.2 equiv) was added after 2 hours. The resulting solution was stirred for 3 h at 100° C. The reaction mixture was cooled to room temperature and diluted with 1000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8). This resulted in 81 g (35.7%) of methyl 4-[3-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-methoxyphenyl]-3-methylbenzoate as a yellow solid. LCMS (ES, m/z): 411 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 8.398 (1H, s), 7.976 (1H, s), 7.916 (2H, d), 7.410 (1H, d), 7.284-7.325 (1H, m), 7.066-7.114 (2H, m), 4.583 (2H, s), 3.954 (3H, s), 3.853 (3H, s), 2.663 (3H, s).

Provenance & Evidence