3788-94-1

51135-73-0

General procedure for the synthesis of ethyl 5-methyl-4-isoxazolecarboxylate from ethyl 2-ethoxymethyleneacetoacetate: ethyl 2-ethoxymethyleneacetoacetate (110.00 g, 0.59 mol) was dissolved in methanol (330 ml) and cooled down to -0 °C. At -5 to 0°C, 50.0% aqueous hydroxylamine (39.03 g, 0.59 mol anhydrous) was slowly added, and the addition time was controlled within 1 hour. After addition, stirring was continued at -0 °C for 30 min. Subsequently, the reaction mixture was warmed up to 20-30 °C and refluxed for 1 hour. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was cooled to room temperature. Hexane (500 ml) was added to the residue and stirred for 30 minutes. Then, saturated sodium bicarbonate solution (100 ml) and water (400 ml) were added sequentially, stirred thoroughly and left to stratify. The organic layer was separated and the aqueous layer was re-extracted with hexane (2 x 200 ml). All organic layers were combined and washed with water (2 x 250 ml). Finally, the solvent was removed under reduced pressure to give a yellow thick oil-like product of ethyl 5-methyl-4-isoxazolecarboxylate 72.5 g in 79% yield, with HPLC purity of 98.7% and isomer impurity content below 0.5%.

references:

[1] Patent: WO2007/86076, 2007, A2. Location in patent: Page/Page column 5-7

[2] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 912 - 920

[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 1875 - 1880

[4] Asian Journal of Chemistry, 2010, vol. 22, # 2, p. 1503 - 1506