The general procedure for the synthesis of 1-methyl-(R)-3-aminopiperidine from (R)-3-Boc-aminopiperidine was as follows:
1. sodium cyanoborohydride (4.51 g, 0.075 mol) was added batchwise to a mixture of tert-butyl (R)-piperidin-3-ylcarbamate (10 g, 0.05 mol), 30% aqueous formaldehyde (7.5 mL) and methanol (75 mL) at 0 °C.
2. The reaction mixture was stirred at room temperature overnight followed by vacuum concentration.
3. The residue was dissolved in a solvent mixture of ethyl acetate and water. After extraction, the organic layer was washed sequentially with water and brine and dried with anhydrous sodium sulfate.
4. Vacuum concentrating the organic layer to obtain the N-methyl compound as an oil, which can be used in the next reaction without further purification.
5. The above crude product was dissolved in methanol (60 mL) and 4N HCl in dioxane solution (10 mL) was added.
6. The reaction mixture was stirred at room temperature for 6 hours, followed by vacuum concentration.
7. The residue was ground with ether, and the resulting precipitate was filtered and washed with ice-cold methanol to yield 1-methyl-(R)-3-aminopiperidine as a solid (4.01 g, 72% yield).
1H NMR (CD3OD, 400 MHz) δ 3.54 (1H, m), 2.81 (1H, m), 2.62 (1H, m), 2.23 (3H, s), 1.97 (1H, m), 1.67-1.87 (3H, m), 1.56-1.61 (1H, m), 1.41 (9H, s), 1.15-1.42 (1H , m).
