Dimethylformamide → Ethyl 6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 100 mL 3-neck flask and a stir bar were dried in oven overnight and then cooled under nitrogen. The reaction was kept under a nitrogen atmosphere through its entirety. 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (10.0 g, 28.9 mmol, Preparation #C.1) was added to the 3-neck flask and dissolved in THF (90 mL). The reaction mixture was cooled to about −30° C. and then a solution of i-PrMgCl (2.0 M in THF, 15.9 mL, 31.8 mmol) was added dropwise. The reaction mixture continued stirring at about −30° C. for about 15 min. In a separate flask, zinc chloride (4.73 g, 34.7 mmol) was dissolved in THF (40 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise (over about 30 min) to the reaction mixture to form a dark yellow suspension. The reaction mixture was stirred at about −30° C. for about 45 min. A third flask was charged with ethyl 6-iodo-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (9.19 g, 28.9 mmol) and DMF (80 mL). To the suspension was added Pd(PPh3)4 (2.00 g, 1.73 mmol) and the suspension was immediately poured into the reaction mixture. The reaction mixture was heated to about 80° C. for 15 min. The mixture was cooled and the DMF was removed under vacuum. The resulting solid was triturated with 1-propanol (20 mL) and filtered to afford a white solid. The material was taken up in DCM (250 mL) and washed with dilute aqueous NaHCO3 (250 mL). The organics were dried and solvent was removed in vacuo to afford the title compound (6.90 g, 16.8 mmol, 58%). LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 411.2 (M+1)+. 1H NMR (DMSO-d6) δ 8.60 (m, 1H), 8.42 (m, 1H), 8.33 (m, 1H), 7.75 (m, 1H), 7.54-7.46 (m, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 4.55 (q, 2H), 1.43 (t, 3H).

Provenance & Evidence