Synthesis
B. Preparation of tert-butyl 3-acetylazetidine-1-carboxylate (C56). A solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (C55) (27.1 g, 0.111 mol) in tetrahydrofuran (THF) (200 mL) was slowly added dropwise to a mixture of 1.4 M methylmagnesium bromide in a mixture of tetrahydrofuran and toluene (25:75) (99.0 mL, 0.139 mol) for a controlled dropwise time of 40 min while maintaining the reaction temperature at about 0 °C. After the dropwise addition, the reaction mixture was stirred at 10-15°C for 2 hours, followed by continued stirring at room temperature for 1 hour. Upon completion of the reaction, the mixture was cooled to 0 °C and the reaction was quenched with 10% aqueous citric acid (150 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (EtOAc) (2 x 300 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (2×250 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: chloroform) to afford the target compound C56. yield: 20.6 g, 0.10 mol, 93% yield.1H NMR (400 MHz, CDCl3): δ 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1H), 2.16 (s, 3H), 1.42 (s, 9H) .
References
[1] Patent: US2010/190771, 2010, A1. Location in patent: Page/Page column 31-32
[2] Patent: WO2010/131145, 2010, A1. Location in patent: Page/Page column 87
[3] Patent: US2015/361067, 2015, A1. Location in patent: Paragraph 0621
[4] Patent: WO2018/137573, 2018, A1. Location in patent: Page/Page column 65; 66
[5] Patent: WO2014/173289, 2014, A1. Location in patent: Paragraph 0296; 0300; 0301
