Quinoxaline-6-acetic acid synthesis

Yield:-

Reaction Conditions:

Stage #1: 2-quinoxalin-6-ylmalonic acid diethyl esterwith methanol;sodium hydroxide;water at 20;
Stage #2: with hydrogenchloride in water;

Steps:

71.b

A solution of 6-iodo-quinoxaline (0.323'g, L26mmol), malonic acid diethyl ester (0.404g, 2.52mmol), copper iodide (0.0i2g, 0.063mmol), biphenyl-2-ol (0.02 Ig,0.126mmol) and cesium carbonate (0.616g, 1.89mmol) in THF (5mL) was heated to 70⁰C in a sealed tube for 24 hours. The solution was then cooled to room temperature, water was added and the crude product was extracted from ethyl acetate. The product was purified via silica gel column chromatography in hexane: ethyl acetate (1:1) to give 2-quinoxalin-6-yl-malonic acid diethyl ester. 2-quinoxalin-6-yl-malonic acid diethyl ester (0.066g, 0.229mmol) was added to a solution of sodium hydroxide [2N] (0.229mL) in methanol (2mL) and stirred for several hours at room temperature. The reaction was then evaporated in vacuo, IN HCl was added and the product was extracted with ethyl acetate to give 0.030g (70%) of quinoxalin-6-yl -acetic acid. ¹H NMR (400 MHz, DMSO-d6) δ 12.6 (bs, IH), 8.93 (dd, 2H, J=2.0, 6.0Hz), 8.05 (d, IH, 8.8Hz), 7.99 (m, IH), 7.79 (dd, IH, J=2.0, 8.8Hz), 3.89 (s, 2H).

References:

WO2007/75567,2007,A1 Location in patent:Page/Page column 131-132