5-Cyano-2,6-dihydroxy-nicotinic acid ethyl ester synthesis

Yield:-

Reaction Conditions:

Stage #1: cyanoacetic acid amidewith sodium in ethanol at 80; for 1.08333 h;
Stage #2: diethyl (ethoxymethylene)malonate in ethanol; for 16 h;Heating / reflux;

Steps:

113.a

Na (2.76 g, 120 mmol) was added piecewise to 22 mL ethanol and was heated at 80 ⁰C for 45 minutes. This was added to a slurry of 2-cyanoacetamide (4.2 g, 50 mmol) in 6 mL warm EPO ethanol. The mixture was stirred for 20 min. followed by addition of diethyl (ethoxymethylene)malonate (10.8 g, 50 rnmol). The reaction mixture was refluxed for 16h followed by cooling to room temperature. The crude product was filtered off and the solid material was triturated with 2x20 mL diethyl ether followed by 2x20 mL heptane. The solid was dried under vacuum to give ethyl 5-cyano-6-hydroxy-2-oxo-l,2-dihydropyridine-3- carboxylate ¹HNMR (500 MHz, DMSO-d6): δ?.O5 (3H,t, J=7Hz ), 3.40(2H, d, J=7Hz), 7.88 (IH, s)

References:

WO2007/8140,2007,A1 Location in patent:Page/Page column 184-185