To an oven-dried 100 mL round-bottomed flask were added N-tert-butoxycarbonyl-L-alanine (3.0 g, 15.8 mmol), anhydrous CH2Cl2 (60 mL), and N,N-diisopropylethylamine (DIPEA, 2.5 mL, 14.2 mmol), and the resulting solution was cooled to 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 3.7 g, 19.0 mmol) and 1-hydroxybenzotriazole (HOBt, 2.6 g, 19.0 mmol) were added in batches over a period of 10 min at 0 °C. The mixture was stirred at 0 °C for 10 min, then N,O-dimethylhydroxylamine hydrochloride (1.9 g, 19.0 mmol) and DIPEA (3.3 mL, 19.0 mmol) were added. The mixture was continued to be stirred at 0 °C for 1 h, followed by warming up to 25 °C and kept for 16 h. The reaction was carried out at 0 °C. Upon completion of the reaction, the reaction mixture was diluted with CH2Cl2 (300 mL) and the organic layer was washed sequentially with 2N HCl (3 × 180 mL), saturated NaHCO3 solution (2 × 180 mL) and brine (2 × 180 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a white solid amide product (3.6 g, 99% yield), which did not require further purification. Product characterization data: mp(CHCl3) 138-140 °C; 1H NMR (300 MHz, DMSO) δ 1.11 (d, J = 6.9 Hz, 3H), 1.33 (s, 9H), 3.07 (s, 3H), 3.69 (s, 3H), 4.36 (t, J = 6.9 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H); ESI MS: 4.36 (t, J = 6.9 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H). 1H); ESI MS: m/z 255 (M + Na)+.
The above amide product (3.7 g, 15.8 mmol) was dissolved in anhydrous THF (100 mL) and cooled to 0°C. Lithium aluminum hydride (LiAlH4, 660 mg, 17.4 mmol) was added to this solution and the reaction was stirred for 20 min. After the completion of the reaction was monitored by TLC, the reaction was quenched with 5% HCl solution. The organic layer was evaporated and the aqueous phase was extracted with EtOAc (3 x 30 mL). The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl (R)-1-(methoxy(methyl)amino)-1-oxo-2-propylcarbamate as a white solid (2.6 g, 94% yield), which did not require further purification. Product characterization data: mp(CHCl3) 82-84 °C; 1H NMR (300 MHz, DMSO) δ 1.09 (d, J = 7.5 Hz, 3H), 1.36 (s, 9H), 3.83 (t, J = 9.9 Hz, 1H), 7.33 (d, J = 5.7 Hz, 1H), 9.39 (s, 1H); ESI MS: m/z 173 (M + H)+, 196 (M + Na)+.
