HCID 57929876, compound → HCID 68992238, compound

Participants

Reaction Conditions

Reaction Steps

In a dry three-neck flask, 3-bromo-2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (1.00 g, 3.09 mmol, prepared using General Procedure C.1 from 2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (prepared according to WO 2007/028051, Preparation #K.1) with NBS) was dissolved in THF (10 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to about −30° C. and then i-PrMgCl (2.0 M in THF, 1.90 mL, 3.80 mmol) was added drop-wise. The reaction mixture was stirred at about −30° C. for about 15 min. In a separate dry flask, zinc chloride (0.57 g, 4.2 mmol) was dissolved in THF (5 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise to the heteroaryl Grignard mixture. The reaction mixture was stirred at about −15° C. for about 30 min. A flask containing 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.85 g, 2.9 mmol; Preparation #H.1) and Pd(Ph3P)4 (0.14 g, 0.12 mmol, Strem) in DMF (10 mL) was stirred at about 80° C. until all of the solids were in solution. This solution was poured into the zincate suspension and the mixture was immediately heated to about 50° C. in an oil bath. After heating at about 50° C. for about 18 h, the mixture was cooled to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), washed with water (5×100 mL), washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography using DCM/MeOH (gradient, 100:0 to 95:5) as eluent. The solid was then dissolved with heating in MeOH, sonicated, concentrated under reduced pressure to dryness under reduced pressure, then dried in a heated vacuum oven (about 60° C.) to afford a cream solid as the title compound (0.37 g, 29%): LC/MS (Table 1, Method a) Rt=2.85 min; MS m/z: 406.3 (M+H)+.

Provenance & Evidence