Step C. Synthesis of 1-tert-butyl 3-methyl-5-hydroxypiperidine-1,3-dicarboxylate. To a stirred solution of methyl 5-hydroxypiperidine-3-carboxylate (300 g, 1.89 mol) in methanol (3 L) at 0 °C, triethylamine (TEA, 382.5 g, 3.78 mol) and di-tert-butyl dicarbonate (Boc2O, 412 g, 1.89 mol) were added sequentially. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (DCM, 3 L). The diluted mixture was washed with saturated aqueous sodium bicarbonate solution (2L). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 500 mL). The organic layers were combined, washed sequentially with water (1 L) and brine (500 mL), dried with anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. Purification by fast column chromatography (FCC, silica gel column, petroleum ether/ethyl acetate, 30:1 to 5:1) afforded methyl 1-Boc-5-hydroxy-3-piperidinecarboxylate (170 g, 35% yield) as a brown solid. 1H NMR (CDCl3, 400MHz) δ 3.95-4.04 (m, 1H), 3.71 (s, 3H), 2.93-3.11 (m, 2H), 2.89-2.92 (m, 1H), 2.57 (bs, 1H), 2.21-2.34 (m, 1H), 2.00-2.12 (m, 1H), 1.75- 1.87 (m, 1H), 1.58-1.71 (m, 1H), 1.46 (s, 9H).
