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

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A ˜1:1 mixture 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (4.7 g, 18.6 mmol) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (2.65 mL 30.4 mmol) followed by N,N-dimethylformamide (0.08 mL, 1.034 mmol). The reaction mixture was heated at 65° C. for 5 hours, concentrated and dried under high vacuum for 1 hr and taken into the next step without further purification. The crude mixture of acid chloride was suspended in DCE (100 mL) and treated with 3-fluoropyridin-4-amine (2.73 g, 24.31 mmol) and N,N-diisopropylethylamine (5.31 mL, 30.4 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered through Buchner funnel, washed with DCE (2×25 mL) to isolate a 1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (5.2 g, 15.0 mmol, 80% yield) as light brown 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=1.1 (M+H=326.07 and M+H=372.01).

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