Potassium Phosphate, Dibasic → Ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

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Reaction Conditions

Reaction Steps

A 2L 3-neck flask was charged with 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (50 g, 226 mmol) and dry toluene (750 ml). POCl3 (41.6 g, 271.5 mmol) was added in one portion, followed by slow addition of DIEA (32.2 g, 248.9 mmol) at a rate, which maintained the temperature below 30° C. The resulting suspension was heated to 111° C. for 24 h becoming homogeneous at 80° C. The reaction was monitored by HPLC after quenching with 2 M MeNH2/THF (10 μl reaction mixture, 20 μl MeNH2/THF in 200 μl acetonitrile). Upon completion, reaction was cooled to −8° C. and a solution of K2HPO4 in H2O (170 g/775 ml) was added maintaining temperature below 1° C. The mixture was stirred for 20 min at −8° C. then warmed to ambient temperature for 1 h. The resulting light suspension was filtered through a pad of celite and the layers were separated. The organic layer was washed with K2HPO4 in H2O (27 g/130 ml), followed by water (250 ml) and dried (Na2SO4). The solution was filtered and concentrated to a yellow foam 4A (54.0 g, 100%). MS: 235 (MeNH2 adduct) (M+H)+; HPLC Ret Time (MeNH2 adduct): 2.240 min (YMC S5 ODS 4.6×50 mm column, 4 min gradient, 3 mL/min).

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