Dimethylformamide → 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

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A ˜1:1 mixture of 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (2.0 g, 8.62 mmol) was suspended in DCE (20 mL), and treated with neat oxalyl dichloride (4.37 g, 34.5 mmol) followed by N,N-Dimethylformamide (0.534 mL, 6.90 mmol). The reaction mixture was heated at 70° C. for 6 hours, concentrated and dried under high vacuum for 1 hr and taken to the next step without further purification. The crude mixture of acid chloride was suspended in DCM (10 mL) and treated with 2-fluoropyridin-4-amine (1.0 g, 8.92 mmol) and triethylamine (3.75 mL, 26.8 mmol) and stirred at room temperature for 14 hours. The reaction mixture was filtered through a Buchner funnel, and washed with water (2×25 mL) to isolate 1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (1.18 g, 8.92 mmol, 40.5% yield) as yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.47 (M+H=326.1 and M+H=372.04).

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