Hydrochloric Acid → cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

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Reaction Steps

2-(2-Fluoro-4-(trifluoromethoxy)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.07 g, 11.14 mmol) (reference compound 25) was dissolved in methyl THF (100 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.71 g, 16.71 mmol) was added. The suspension was stirred at room temperature for 5 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (3.41 g, 20.06 mmol) suspended in methyl THF (50 mL) and magnesium chloride (1.910 g, 20.06 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 15 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (gradient 3:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (3.44 g, 70.9%) and trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (0.420 g, 8.66%) were isolated as colorless oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.23-1.28 (m, 3H), 1.77-1.96 (m, 2H), 2.03-2.14 (m, 1H), 2.24-2.31 (m, 1H), 2.84-2.93 (m, 1H), 3.32-3.48 (m, 3H), 3.57-3.65 (m, 3H), 4.08-4.20 (m, 3H), 5.03-5.12 (m, 1H), 6.89-6.98 (m, 2H), 7.13-7.21 (m, 1H). MS m/z 436 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.16-1.28 (m, 3H), 1.62 (dq, 1H), 1.85-2.00 (m, 2H), 2.37-2.60 (m, 2H), 3.12 (dt, 1H), 3.43 (s, 2H), 3.68 (s, br., 3H), 4.08-4.20 (m, 2H), 4.25 (s, br., 1H), 5.68 (s, br., 1H), 6.92-7.01 (m, 2H), 7.13 (t, 1H). MS m/z 436 (M+H)+

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