Reaction Steps
1-(Methoxycarbonyl)-2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylic acid (4.756 g, 13.93 mmol) was dissolved in methyl THF (70 mL) and di(1H-imidazol-1-yl)methanone (3.39 g, 20.90 mmol) added. A thick white precipitate was formed. methyl THF (70.0 mL) was added and the suspension stirred under nitrogen at room temperature for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.74 g, 27.86 mmol) was suspended in methyl THF (70.0 mL) and magnesium chloride (2.65 g, 27.86 mmol) added. Heated at 50° C. under nitrogen for 6 h (flask 2). The white suspension in flask 2 was then added to the thick white suspension in flask 1. The suspension was stirred at room temperature for 16 h. The temperature was increased to 50° C. for 6 h. More of potassium 3-ethoxy-3-oxopropanoate (4.74 g, 27.86 mmol) and magnesium chloride (2.65 g, 27.86 mmol) in MeTHF (15 mL) was added along with dioxane (60 mL). The reaction was stirred at 50° C. for 18 h. The reaction mixture was acidified to pH 1 with 3 M HCl. The organic phase was washed with water (2×400 mL), satd NaHCO3 (400 mL), brine (400 mL), dried with Na2SO4, filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 50% EtOAc in heptane over 2 CV followed by 50% to 80% of EtOAc in heptane over 10 CV was used as mobile phase. Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (2.70 g, 47.1%) and trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)-piperidine-1-carboxylate (0.505 g, 8.81%) were isolated. Cis-isomer: NMR: 1H NMR (600 MHz, CDCl3) δ 1.25 (t, 3H), 1.80-1.95 (m, 2H), 2.04-2.16 (m, 1H), 2.23-2.32 (m, 1H), 2.84-2.95 (m, 1H), 3.02 (s, 3H), 3.29-3.38 (m, 1H), 3.38-3.48 (m, 2H), 3.63 (s, 3H), 4.10-4.21 (m, 3H), 4.95-5.04 (m, 1H), 7.40 (d, 2H), 7.88 (d, 2H). MS m/z 410 (M−H)−. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.23 (t, 3H), 1.12-2.26 (m, 3H), 2.51-2.62 (m, 2H), 2.83 (td, 1H), 3.04 (s, 3H), 3.40-3.48 (s, 2H), 3.75 (s, 3H), 4.07-4.38 (m, 1H), 4.15 (q, 2H), 5.49-5.77 (m, 1H), 7.41 (d, 2H), 7.93 (d, 2H). MS m/z 412 (M+H)+
