Synthesis
Step 1: Synthesis of tert-butyl 3-oxomorpholine-4-carboxylate
3-Morpholinone (35 g, 346.2 mmol) was suspended in anhydrous tetrahydrofuran (350 mL). Di-tert-butyl dicarbonate (105.8 g, 484.7 mmol) and 4-dimethylaminopyridine (4.2 g, 34.6 mmol) were added sequentially. The reaction mixture started to release gas vigorously within 30 minutes. The resulting orange solution was stirred at room temperature for 24 hours. Subsequently, the mixture was cooled in an ice bath and imidazole (23.57 g, 346.2 mmol) was added. After stirring for 30 minutes, the mixture was diluted by adding ethyl acetate (500 mL). The organic phase was separated and washed sequentially with 1% (v/v) hydrochloric acid (500 mL), saturated sodium bicarbonate solution (500 mL) and brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate as eluent. The eluate was collected and concentrated to give an oil. 40/60 petroleum ether (200 mL) was added slowly and a white solid was precipitated with stirring. The mixture was aged for 30 minutes, cooled briefly in an ice bath, filtered and washed with 40/60 petroleum ether. Vacuum drying gave tert-butyl 3-oxomorpholine-4-carboxylate as a white solid (52.7 g, 76% yield).
1H-NMR (CDCl3) δ: 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s).
MS ES (+) m/z: 145.8 (M+ -tBu).
References
[1] Patent: WO2013/49719, 2013, A1. Location in patent: Paragraph 00197
[2] Patent: WO2017/12576, 2017, A1. Location in patent: Page/Page column 177
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 16, p. 2928 - 2938
