1-Hydroxybenzotriazole → 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

Participants

Reaction Steps

A solution of trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed by reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (216 mg) as a colourless oil.

Provenance & Evidence