Sulfuric Acid → Ethyl 2-[2-(acetylamino)pyridin-4-yl]-4-hydroxy-1,3-thiazole-5-carboxylate

Participants

Reaction Conditions

Reaction Steps

To a suspension of N-(4-carbamothioylpyridin-2-yl)acetamide (15 g, 77 mmol) produced in the same manner as in Example 1(ii) in 2-propanol (136 mL) was added ethyl 2-chloro-3-oxo-3-phenylpropanoate, and the mixture was stirred with heating at 90° C. for 12 hr. Tetrabutylammonium bromide (1.2 g, 3.9 mmol) was added to the reaction solution, and the mixture was further stirred with heating at the same temperature for 10 hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL), and saturated aqueous sodium bicarbonate solution (200 mL) was added. The resulting solid was collected by filtration, and washed with water (200 mL), ethanol (100 mL) and diethyl ether (100 mL×2). The obtained crude product was suspended in acetic anhydride (150 mL), concentrated sulfuric acid (0.05 mL) was added, and the mixture was heated under reflux at 120° C. for 2 hr. The reaction mixture was cooled to room temperature, and acetic anhydride was evaporated under reduced pressure. The residue was suspended in methanol (50 mL), and after stirring, methanol was evaporated under reduced pressure. The obtained residue was suspended in tetrahydrofuran (300 mL), 25% aqueous ammonia solution (150 mL) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added methanol (100 mL), and the mixture was further stirred at room temperature for 30 min. The resulting solid was collected by filtration, and washed with water (100 mL) and diethyl ether (100 mL) to give the title compound (7.4 g, 31%) as a yellow solid. The combined filtrate and washing solution was concentrated under reduced pressure, the resulting yellow solid was collected by filtration, and washed with water (500 mL), ethanol (100 mL) and diethyl ether (200 mL) to give a second crop (2.9 g, 12%) of the title compound as a yellow solid.

Provenance & Evidence