Lithium Hydroxide → 2-(Benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide

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Reaction Steps

A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield.

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