Synthesis
GENERAL STEPS: (S)-2-methyl-1-((S)-1-phenylethyl)piperidin-4-one hydrochloride (200 g, about 1.2855 moles free base) was dissolved in water (500 mL). The solution was added to a mixture of dichloromethane (1 L) and aqueous sodium bicarbonate (180 g NaHCO3 dissolved in 1.2 L of water) at room temperature. Subsequently, a solution of dichloromethane (500 mL) of di-tert-butyl dicarbonate (280 g, 1.28 mol) was added, and the reaction mixture was stirred at 20°C overnight. The aqueous layer was separated and extracted twice with dichloromethane (500 mL). The organic layers were combined, washed with water (500 mL), dried over anhydrous magnesium sulfate (60 g), filtered and concentrated in vacuum to give a red oil (276.5 g). The oil was dissolved in cyclohexane (1 L) and filtered through a silica gel (300 g) column. It was sequentially eluted with cyclohexane (2L) and cyclohexane/ethyl acetate (1:1, 1L). The filtrate was concentrated in vacuum to afford 1-N-Boc-2(S)-methyl-piperidin-4-one as a yellow solid (261 g, 95% yield).
Alternative steps: in a one-pot synthesis, N-(S)-1-phenylethyl-2(S)-methyl-piperidin-4-one (200 g, 0.9208 mol) was dissolved in tetrahydrofuran (200 mL), and a tetrahydrofuran (200 mL) solution of di-tert-butyl dicarbonate (214.7 g, 0.9838 mol) was added. The reaction mixture was protected with nitrogen and a palladium/carbon catalyst (10% Pd/C, dry, 10 g) was added. The reactor was displaced three times with nitrogen and then three times with hydrogen. The reaction mixture was heated to 50 °C and hydrogenated overnight under hydrogen pressure (3 bar, ~43.5 psi, 300 kPa) and stirring (300 rpm). The reaction was monitored by thin layer chromatography (TLC, silica gel plates, cyclohexane/ethyl acetate 1:1) until the feedstock completely disappeared. After completion of the reaction, it was cooled to room temperature and displaced three times with nitrogen. The catalyst was removed by filtration through a diatomaceous earth pad and washed with tetrahydrofuran (200 mL). The solvent was evaporated under reduced pressure (40 °C, vacuum) to give the crude product as a yellow oil (183.5 g, 93% yield). The crude product was dissolved in n-hexane (200 mL) and stirred at 20 °C overnight. The solid was collected by filtration, washed with hexane (50 mL) and dried in vacuum at 20 °C to give 1-N-Boc-2(S)-methyl-piperidin-4-one (78 g, 39% yield). The mother liquor was concentrated under reduced pressure to 140 g of residue, cooled and stirred at 20 °C overnight. The suspension was cooled to 5 °C, stirred for 15 min, filtered, washed with hexane (20 mL) and dried under vacuum at 20 °C to afford additional 1-N-Boc-2(S)-methyl-piperidin-4-one (30.6 g, 15% yield).
References
[1] Patent: WO2004/94380, 2004, A1. Location in patent: Page 28; 31-32
[2] Patent: US2012/252778, 2012, A1. Location in patent: Paragraph 0340-0341
