Dimethylformamide → 4-(3-Fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester

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Reaction Conditions

Reaction Steps

1H-Thieno[3,2-d][1,3]oxazine-2,4-dione (14) (40.0 g, 0.24 mol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 21.75 g, 0.54 mol) in 300 mL anhydrous DMF stirred under argon at −10° C. After stirring at −10° C. for 15 minutes, 3-fluorobenzylbromide (29.73 mL, 0.24 mol) was added to the solution. The solution was allowed to come to room temperature and further stirred for 3 hours. The solution was again cooled to −10° C., and diethylmalonate (36.62 mL, 0.24 mol) was added slowly. The solution was then heated at 110° C. for 45 minutes. A large amount of gas evolved very quickly once the solution was heated, so this heating step was done in a flask at least 5 times as large as the reaction volume, and a reflux condenser was used which was open to the air, and not sealed with a septum. The reaction mixture was cooled to room temperature, and poured into a solution of potassium carbonate (32.68 g, 0.24 mol) in 2.5 L of water. This aqueous solution was stirred for 5 minutes, and then it was extracted 2 times with 600 mL ethyl acetate and 2 times with 600 mL isopropyl ether. These organic phases were discarded. The aqueous solution was then acidified slowly to pH 2 with 4M HCl. The precipitated solid product was collected by vacuum filtration to yield 60.1 g (73% yield) of 4-(3-fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.36 (s, 2H), 7.06 (m, 3H), 7.33 (m, 2H), 8.15 (m, 1H), 13.37 (s, 1H) ppm, EIMS m/z 348 (M+1).

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