Dimethylformamide → 5-(3-Isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole

Temperature

-65 °C

A 50-mL round bottom flask was charged with 5-iodo-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (0.65 g, 1.8 mmol) and THF (4.5 mL) to give a white suspension. The mixture was cooled to about −65° C. followed by the addition of a 2.0 M solution of i-PrMgCl (1.1 mL, 2.1 mmol). The resulting suspension was stirred at about −55° C. for about 30 min and at about −30° C. for about 1.75 h. To the reaction mixture was added dropwise a prepared solution of zinc chloride (0.32 g, 2.3 mmol) in THF (3.0 mL) and the resulting suspension was stirred at about −30° C. for about 30 min. In a separate flask were mixed 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.49 g, 1.7 mmol, Preparation #H.1), Pd(PPh3)4 (Strem, 0.073 g, 0.071 mmol), and DMF (5.0 mL). This solution was added to the reaction flask, which was immediately heated to about 80° C. in order to solubilize the resulting mixture. The mixture was heated at about 80° C. for about 1 h. The cooled reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in DCM and washed with 1 N HCl, 5 N HCl, water, and brine. The solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude product was recrystallized from ACN to give a light yellow powder, followed by RP-HPLC (Table 1, Method l) purification to give the title compound as an off-white powder (0.025 g, 3.5%): LC/MS (Table 1, Method a) Rt=2.47 min; MS m/z 399.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1 H), 8.26 (d, 1 H), 8.22 (d, 1 H), 7.85-7.71 (m, 2 H), 7.07 (dd, 1 H), 3.73-3.66 (m, 1 H), 1.44 (d, 6 H).

1. customto give a white suspension
2. stirringthe resulting suspension was stirred at about −30° C. for about 30 min
3. additionThis solution was added to the reaction flask, which
4. temperaturewas immediately heated to about 80° C. in order
5. temperatureThe mixture was heated at about 80° C. for about 1 h
6. customThe cooled reaction mixture
7. concentrationwas concentrated to dryness under reduced pressure
8. dissolutionthe residue was dissolved in DCM
9. washwashed with 1 N HCl, 5 N HCl, water, and brine
10. dry with materialThe solution was dried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated to dryness under reduced pressure
13. customThe crude product was recrystallized from ACN
14. customto give a light yellow powder
15. customfollowed by RP-HPLC (Table 1, Method l) purification

ORD record

ord-7fd8aa65a184497187efca5d9f8ed1eb

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08188083B2