1-N-Boc-3-(S)-Methylamino-piperidine

Synthesis

General procedure for the synthesis of 1-N-BOC-3-(S)-methylaminopiperidine from formaldehyde and (S)-1-Boc-3-aminopiperidine: tert-butyl (5.0 g, 25 mmol) of (S)-3-aminopiperidine-1-carboxylate (5.0 g, 25 mmol) was added to a stirred aqueous formaldehyde (1.85 mL, 25 mmol, 37%) and suspension of molecular sieves in methanol and the reaction mixture was stirred at room temperature (24 °C) the reaction mixture was stirred for 24 hours. Subsequently, sodium borohydride (1.52 g, 40 mmol) was slowly added to the above mixture at room temperature and stirring was continued for 16 hours. Upon completion of the reaction, the reaction was quenched by the addition of ice water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to afford 3.0 g of the crude product (S)-tert-butyl 3-(methylamino)piperidine-1-carboxylate as a light yellow liquid, which was used directly in the next step of the reaction.1H NMR (400 MHz, CDCl3) δ ppm: 1.38 (s, 9H), 1.5-1.7 (m, 4H), 1.71-1.90 (m 2H), 2.18-2.27 (m, 3H), 2.75-2.90 (m, 1H), 3.50-3.92 (m, 2H).

References

[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1061 - 1073
[2] Patent: WO2018/2437, 2018, A1. Location in patent: Page/Page column 99