Tetrahydrofuran → Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate

Participants

Reaction Steps

A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25 g, 38.8 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem LLC, Monmouth N.J.) (8.28 g, 58.3 mmol) in tetrahydrofuran (400 mL, 38.8 mmol) contained in an oven dried 1 L 3-neck round-bottomed flask equipped with N2 inlet was stirred at a temperature between −5° C. and −10° C. and treated dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (117 mL, 117 mmol). The dark pink solution was stirred between −5° C. and −10° C. for 1 h. The reaction was quenched with water (100 mL) and NH4Cl (100 mL) and diluted with EtOAc (350 mL). The separated aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (26.8 g, 35.0 mmol, 90% yield). m/z (ESI, positive ion) m/z 766 (M+H)+.

Provenance & Evidence