Synthesis
Sodium hydride (5.12 g, 213 mmol) was suspended in anhydrous tetrahydrofuran (250 mL) under argon protection and stirred at 50 °C. Subsequently, a mixture of ethyl acetate (15.3 mL, 156 mmol) and ethyl 2,2-diethoxyacetate (25 mL, 142 mmol) was slowly added dropwise over 30 min. After dropwise addition, the reaction mixture was refluxed for 4 hours, followed by cooling to room temperature and continued stirring for 16 hours. Upon completion of the reaction, the mixture was concentrated to about one-third of the original volume by rotary evaporation, and then a 15% v/v aqueous solution of acetic acid (about 145 mL) was added rapidly at 0 °C. Extraction was carried out with ether (4×100 mL), and the organic phases were combined and washed sequentially with water (1×20 mL), saturated aqueous sodium carbonate solution (3×50 mL), water (2×20 mL), and brine (1×30 mL), and finally dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the target product ethyl 4,4-diethoxy-3-oxobutanoate (Scheme 1, A) was obtained as a clear yellow oil with a keto-enol interconversion isomer ratio of 4:1 (25.05 g, 81% yield). The product was characterized by 1H NMR (300 MHz, CDCl3): δ 1.22-1.30 (m, 9H), 3.53-3.76 (m, 5.6H), 4.19 (q, J = 7.6 Hz, 2H), 4.67 (s, 0.8H), 4.92 (s, 0.2H), 5.45 (s, 0.2H), 11.88 (s, 0.2H ).
References
[1] Patent: WO2010/106016, 2010, A1. Location in patent: Page/Page column 125-126
[2] European Journal of Organic Chemistry, 2013, # 19, p. 3965 - 3969
[3] Patent: WO2007/58582, 2007, A1. Location in patent: Page/Page column 49-50
[4] Journal of Organic Chemistry, 1998, vol. 63, # 5, p. 1668 - 1675
[5] Journal of medicinal chemistry, 1963, vol. 6, p. 283 - 288
