Hydrochloric Acid → N-ethyl-4-azido-3-benzyloxybenzamide

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Reaction Steps

N-Ethyl-4-amino-3-benzyloxybenzamide (1.52 g, 5.62 mmol) obtained in Example 312c) was dissolved in water (20 ml) and acetic acid (10 ml), 1N hydrochloric acid (5.62 ml, 1.0 eq.) was added. An aqueous solution (5 ml) of sodium nitrite (394 mg, 5.62 mmol, 1.0 eq.) was added at 0° C., and the mixture was stirred for 30 min. An aqueous solution (5 ml) of sodium azide (373 mg, 5.62 mmol, 1.0 eq.) was further added, and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was diluted with ethyl acetate-hexane (3:1, 80 ml), washed sequentially with water, 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness to give N-ethyl-4-azido-3-benzyloxybenzamide as a yellow powder (1.64 g). This powder (1.64 g) and ethyl 4-benzyloxy-3-oxobutyrate (1.35 g, 5.71 mmol) were dissolved in ethanol (40 ml), sodium ethoxide (454 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 14 hr. 1N sodium hydroxide (5.71 ml) was added to the reaction mixture, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water (30 ml), ethanol was evaporated, and the residue was diluted with water (40 ml) and washed with ethyl acetate-hexane (2:1, 90 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (50 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (90 ml and 50 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give a pale-brown solid (purity about 90%, 2.10 g, 3.9 mmol, 69%).

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