反应详情

温度

70 °C

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.

1. customA 5 l round-bottomed flask equipped with a mechanical stirrer
2. customCycling vacuum and then nitrogen three times degassed the stirred slurry
3. dissolutionAll solids dissolved
4. customA 500 ml round-bottomed flask equipped with a magnetic stir bar
5. customThe resulting solution was degassed as above, then tri-tert-butylphosphine (49.8 ml of a 10 wt % solution in hexanes
6. addition16.7 mmol) was added by syringe
7. customThe solution was degassed again
8. temperaturewarmed to 70° C
9. customAt the end of reaction
10. custommost of the product had crystallized out
11. customto provide a grey slurry
12. customThe reaction mixture was partitioned between 2N HCl (1.8 l) and toluene (0.9 l)
13. additionwas added
14. customAfter 90 min the resulting black solids were removed by filtration through a 1.0μ
15. filtrationfilter
16. customequipped with a pH probe
17. additionThe pH was adjusted to 3.8 by slow addition of 50 wt % NaOH (about 130 ml)
18. customThe mixture self-nucleated to provide a slurry
19. customto provide a cream-colored slurry
20. customThe solids were collected on a frit
21. washwashed with water (250 ml) and air
22. customdried