Isopropyl Acetate → 2-[3-(3-Chloro-4-fluorophenyl)imidazo[1,2-alpha]pyrimidin-7-yl]propan-2-ol

Participants

Reaction Conditions

Reaction Steps

A 500 ml round-bottomed flask equipped with a mechanical stirrer, thermocouple and nitrogen/vacuum inlet was charged with 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (10.62 g, 60.0 mmol), 4-bromo-2-chloro-1-fluorobenzene (8.00 ml, 66.0 mmol), palladium(II) acetate (270 mg, 1.20 mmol), triphenylphosphine (630 mg, 2.40 mmol), cesium carbonate (19.6 g, 60.2 mmol), and anhydrous 1,4-dioxane (120 ml). The slurry was degassed using five vacuum/nitrogen back-fill cycles, and then heated to 90° C. and aged for 12 hours. The mixture was cooled to 60° C. then water (150 ml) and EtOAc (150 ml) were added to the crude reaction mixture and the slurry was stirred at 45° C. until all of the solids were dissolved. The layers were partitioned and the aqueous phase was extracted again with EtOAc (50 ml). The organic phases were combined and extracted twice with 2N HCl (100 ml then 30 ml). The acidic aqueous phases were combined with EtOAc (250 ml) and NaOH (10.9 g, final pH=10) was added slowly with stirring and the mixture was warmed to 65° C. to dissolve the solids. The phases were separated and the organic phase was concentrated to about 200 ml to provide a slurry. Isopropyl acetate (110 ml) was added and the slurry was concentrated again to about 200 ml. The slurry was warmed to 90° C. then cooled over several hours to 0° C. The crystalline solids were collected on a frit, rinsed with isopropyl acetate/EtOAc (1:1) and air dried to provide 2-[3-(3-chloro-4-fluorophenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol (16.19 g) as a cream-colored crystalline solid: m.p. 180-182° C.; 1H NMR (CDCl3, 400 MHz) δ 8.53 (1H, d, J 7.2), 7.86 (1H, s), 7.59 (1H, dd, J 6.8, 2.0), 7.42 (1H, m), 7.34 (1H, m), 7.14 (1H, d, J 7.2), 1.63 (6H, s); 13C NMR (CDCl3, 100.64 MHz) δ 167.8, 158.1 (d, J 252.2), 148.0, 133.8, 131.4, 130.0, 127.8 (d, J 7.2), 125.5 (d, J 4.0), 122.4 (d, J 18.5), 122.1, 117.8 (d, J 20.9), 105.7, 72.5, 29.9.

Provenance & Evidence