Diisopropylethylamine → N-[[4-fluoro-2-(methylcarbamoyl)phenyl]methyl]-8-hydroxy-5-(6-methyl-1,1-dioxo-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxamide

Participants

Reaction Steps

8-Hydroxy-5-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxylic acid was coupled with {2-[(methylamino)carbonyl]4 fluorophenyl}methanaminium chloride (prepared as described in Example 3). A solution of 8-hydroxy-5-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxylic acid (200 mg, 0.59 mmol) in dry DMF (2 mL) was stirred at zero degrees. To this was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (147 mg, 0.77 mmol), 1-hydroxy-7-azabenzotriazole (181 mg, 1.18 mmol). The mixture was stirred for 35 minutes at which time the {4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride (194 mg, 0.89 mmol) and diisopropylethylamine (124 μL, 0.7 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was filtered through a glass fiber filter. The filtrate was injected directly into the preparative HPLC (Gilson semi preparative HPLC system using a Waters Nova pak column (10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.025% TFA)/acetonitrile (0.025% TFA) at 35 mL/min). The desired fractions were freeze dried to give the desired product as a white solid.

Provenance & Evidence