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1029714-88-2

74-89-5

1029712-80-8

Example 20 Synthesis of 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15): 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzoic acid (14, 331.4 g, 0.914 mol, 1.0 eq.) and (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP, 570 g, 1.1 mol, 1.2 eq.) were dissolved in N,N-dimethylformamide (DMF, 3700 mL). To this solution, a tetrahydrofuran solution of 2M methylamine (1830 mL, 3.656 mol, 4.0 eq.) was slowly added for 15 min at room temperature. The reaction temperature was raised to 30 °C during the addition and the reaction mixture became homogeneous. Subsequently, triethylamine (TEA, 382 mL, 2.742 mol, 3.0 eq.) was added to the reaction mixture and the reaction mixture was stirred for 2-4 h at room temperature. The progress of the reaction was monitored by LC/MS and after confirming the completion of the coupling reaction, water (950 mL) was added to the reaction mixture. The resulting suspension was cooled to 0-5 °C in an ice bath and stirred at this temperature for 30 min. The solid was collected by filtration and washed with water (200 mL). The wet solid filter cake was suspended in a solvent mixture of water and acetonitrile (1:1 v/v, 2000 mL) and stirred for 1 hour at room temperature. The solid was collected by filtration, washed sequentially with water and acetonitrile, and then dried to constant weight in a vacuum oven at 40-45 °C to afford 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (15, 322 g, 85.4% yield) as a yellow to bright yellow powder.