Ethanol → 3-Amino-3-Oxopropanoic Acid

Participants

Reaction Steps

Ethyl 2-amino-4-methyl-thiophene-3-carboxylate, (27.0 mmol, 5.0 g), was heated in diethyl malonate (25 ml) at 180° C. for 3 hrs, and the formed ethanol was allowed to distil off. The oil bath temperature was lowered and diethyl malonate was distilled off at reduced pressure to give the intermediate malonic amide, 2-(2-ethoxycarbonyl-acetylamino)-4-methyl-thiophene-3-carboxylic acid ethyl ester, as an oil that slowly crystallized upon standing (7.7 g, 95%). The malonic amide was dissolved in N,N-dimethylacetamide, (DMA, 40 ml), and sodium hydride (NaH 80%, 2.0 equiv. 54 mmol, 1.62 g) was added. The mixture was heated at 60° C. for 1 h. After cooling and addition of water (300 ml), the product was precipitated by addition of concentrated hydrochloric acid (HCl) to pH 1.5. The precipitate was collected by filtration and recrystallized from methyl isobutyl ketone giving 6,7-dihydro-4-hydroxy-3-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (3.8 g, 56%). The carboxylic acid ethyl ester, (11.9 mmol, 3.02 g), was dissolved in DMA (40 ml) and NaH (2.1 equiv., 25 mmol, 750 mg) was added. The mixture was heated to 40° C. for 10 min. Thereafter it was cooled to 10° C. and dimethyl sulphate (1.2 equiv., 14.3 mmol, 1.37 ml) was added. The mixture was stirred at ambient temperature for 1 h and then cooled on an ice bath. Water (200 ml) was added and the mixture was acidified with 5 M HCl to pH 1.5. The precipitate was collected and recrystallized from toluene/heptane giving the title compound (2.4 g, 75%).

Provenance & Evidence