Hydrochloric Acid → 2-(4-Methyl-5-nitro-pyridin-2-yl)-chromen-4-one

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Reaction Conditions

Reaction Steps

A solution of 2′-hydroxyacetophenone (1.68 g, 12.39 mmol) in tetrahydrofuran (120 ml) under argon was cooled to −78° C. and treated dropwise with lithium hexamethyldisilazane (1M in tetrahydrofuran, 2.25 ml, 2.25 mmol). The solution was stirred at −78° C. for 1 hour and at −10° C. for 2 hours then cooled down to −78° C. and treated dropwise with a solution of 4-Methyl-5-nitro-pyridine-2-carboxylic acid methyl ester (WO2005/103003) (2.42 g, 12.39 mmol) in tetrahydrofuran (60 ml). The dark red solution was stirred at −78° C. for 1 hour then at room temperature for 18 hours. The mixture was poured into a ice-cold 1 N solution of hydrochloric acid (200 ml) and extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated to dryness. The residue was dissolved in acetic acid (60 ml), treated with sulfuric acid (0.33 ml) and heated to 100° C. for 30 minutes. After cooling to room temperature, the solution was concentrated and the residue added with water and neutralized with a saturated solution of sodium hydrogenocarbonate. The precipitate was filtrated, washed with water and dried under vacuum to yield 2-(4-Methyl-5-nitro-pyridin-2-yl)-chromen-4-one (2.33 g, 66%) as a brown solid. The previous chromen-4-none (770 mg, 2.72 mmol) was treated with tert-butyl-hydroxylamine hydrochloride (685 mg, 5.45 mmol) in methanol (20 ml) at 130° C. for 30 minutes under microwave irradiation (method D, step 1) to yield the title compound (394 mg, 41%) after purification by silica gel flash chromatography (gradient cyclohexane/dichloromethane 0-80%) as a gold solid.

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