Step 1. Synthesis of tert-butyl (6-methylpyridin-3-yl)carbamate. Di-tert-butyl dicarbonate (55.5 g, 298 mmol) was slowly added dropwise to a solution of 6-methylpyridin-3-amine (25 g, 231 mmol) in ethanol (100 mL) at 0 °C. After the dropwise addition, the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (unfolding agent: petroleum ether/ethyl acetate, 2:1) to confirm complete consumption of 6-methylpyridin-3-amine. Upon completion of the reaction, the reaction mixture was filtered and the filter cake was washed with ethanol (30 mL x 3). The filtrates were combined and concentrated under reduced pressure to give a yellow residue. This residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate, 4:1 to 1:1) to afford tert-butyl (6-methylpyridin-3-yl)carbamate (32.5 g, 67.4% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.0 Hz, 1H), 7.86 (br s, 1H) 7.10 (d, J = 8.5 Hz, 1H), 6.57 (br s, 1H), 2.49 (s, 3H), 1.51 (s, 9H). Step 2. Synthesis of racemic-cis/trans-tert-butyl (6-methylpiperidin-3-yl)carbamate. Platinum oxide (2.5 g) was added to a dry hydrogenation flask under argon protection. Then a solution of tert-butyl (6-methylpyridin-3-yl)carbamate (33 g, 158.5 mmol) in acetic acid (300 mL) was added, and the resulting mixture was hydrogenated at 50 °C under 55 psi hydrogen pressure for 30 hours. The progress of the reaction was monitored by TLC (unfolding agent: petroleum ether/ethyl acetate, 2:1) to confirm complete consumption of the starting material. Upon completion of the reaction, the reaction mixture was filtered and the filter cake was washed with methanol (50 mL x 2). The filtrates were combined and evaporated under reduced pressure to afford tert-butyl (6-methylpiperidin-3-yl)carbamate (34 g, 100% yield) as a yellow oil (cis/trans ratio 2:1), which was used directly in the next step of the reaction without further purification.LC/MS (M + H) 215.2.
