Reaction Steps
A 5 l round-bottomed flask equipped with a mechanical stirrer, thermocouple, nitrogen/vacuum inlet adaptor and septum was charged with 2-[3-(3-chloro-4-fluorophenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol (101.59 g, 333 mmol), 3-pyridineboronic acid in the form of its boroxine (42.98 g, 350 mmol), K3PO4 (111.69 g, 526 mmol), 1,4-dioxane (1.20 l), and water (406 ml). Cycling vacuum and then nitrogen three times degassed the stirred slurry. All solids dissolved on warming to 70° C. A 500 ml round-bottomed flask equipped with a magnetic stir bar, thermocouple, nitrogen/vacuum inlet adaptor and septum was charged with bis(dibenzylideneacetone)palladium(0) (9.57 g, 16.7 mmol) and 1,4-dioxane (130 ml). The resulting solution was degassed as above, then tri-tert-butylphosphine (49.8 ml of a 10 wt % solution in hexanes, 16.7 mmol) was added by syringe. The solution was degassed again and then warmed to 70° C. The warm catalyst solution was cannulated to the 5 l flask and the resulting mixture was stirred at 70° C. for 16 h. At the end of reaction, most of the product had crystallized out to provide a grey slurry. The reaction mixture was partitioned between 2N HCl (1.8 l) and toluene (0.9 l). The clear yellow aqueous phase was transferred to a stirred 4 l Erlenmeyer flask with a nitrogen sweep and borane-trimethylamine complex (1.87 g) was added. After 90 min the resulting black solids were removed by filtration through a 1.0μ filter. The filtrate was transferred to a mechanically stirred 5 l flask equipped with a pH probe. The pH was adjusted to 3.8 by slow addition of 50 wt % NaOH (about 130 ml). The mixture self-nucleated to provide a slurry. Additional 50 wt % NaOH (about 36 ml) was added over 30 min to pH 7.1 to provide a cream-colored slurry. The solids were collected on a frit, washed with water (250 ml) and air dried to give the free base 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as an off-white crystalline solid (117.38 g, 94.5 wt % pure): m.p. 234-236° C.; 1H NMR (DMSO-d6, 400 MHz) δ 9.00 (1H, d, J 7.2), 8.85 (1H, bs), 8.60 (1H, dd, J 4.8, 1.6), 8.06 (1H, m), 7.92 (1H, s), 7.87 (1H, dd, J 7.2, 2.4), 7.74 (1H, m), 7.76-7.68 (2H, m), 7.37 (1H, d, J 7.2), 5.49 (1H, s), 1.47 (6H, s); 13C NMR (DMSO-d6, 100.55 MHz) δ 169.6, 159.3 (d, J 248.2), 149.9 (d, J 3.2), 149.6, 148.5, 137.0 (d, J 3.2), 134.0, 133.5, 130.9, 130.3 (d, J 3.2), 130.0 (d, J 8.0), 126.6 (d, J 14.5), 126.1 (d, J 4.0), 124.1, 122.7, 117.7 (d, J 22.5), 106.3, 73.0, 30.3.
