Dimethylformamide → 6-(2,4-Difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)imidazo[2,1-b]thiazole

Participants

Reaction Conditions

Reaction Steps

The 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]thiazole (1.00 g, 2.76 mmol) was suspended in THF (7.5 mL) then cooled to about −30° C. The i-PrMgCl (2 M in THF, 1.52 mL, 3.04 mmol) was added dropwise over about 15 min then stirred at about −30° C. for about 15 min. The ZnCl2 (0.489 g, 3.59 mmol) was dissolved in THF (7.5 mL), cooled to about 0° C., and added dropwise to the Grignard solution. The reaction mixture was stirred for about 30 min at about −30° C. The 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.796 g, 2.76 mmol) was added to DMF (7.50 mL) and heated to about 80° C. to dissolve the material. Pd(Ph3P)4 (0.128 g, 0.110 mmol) was then added to the solution and the mixture was immediately added to the zincate suspension. The mixture was immediately heated to about 55° C. for about 45 min, then cooled, diluted with water and extracted with EtOAc. The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel with DCM/MeOH (95:5) followed by trituration with MeOH (5 mL) gave a solid that was collected by filtration. The filtrate was concentrated under reduced pressure then purified by RP-HPLC using (Table 1, Method d). The desired fractions were concentrated under reduced pressure to give a solid that was collected by filtration. The two crops were combined to give the title compound (0.250 g, 23%): LC/MS (Table 1, Method a) Rt=2.46 min; MS m/z: 397.2 (M+H)+.

Provenance & Evidence