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

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Reaction Steps

1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (5.629 g, 16.99 mmol) (reference compound 13) was dissolved in methyl THF (120 mL) and di(1H-imidazol-1-yl)methanone (4.13 g, 25.49 mmol) added. The suspension was stirred at room temperature under nitrogen for 3 h 45 min (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (5.21 g, 30.58 mmol) was suspended in methyl THF (120 mL) and magnesium chloride (2.91 g, 30.58 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3.5 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase extracted with water, satd NaHCO3 and water. The organic layer was evaporated and traces of water were azeotropically removed by MeCN to yield a brown oil. The diastereoisomers were separated in 2 runs on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.474 g, 7%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (3.532 g, 52%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.26 (t, 3H), 1.72-2.22 (m, 3H), 2.29 (ddd, 1H), 2.83-2.96 (m, 1H), 3.29-3.49 (m, 3H), 3.64 (s, 3H), 4.07-4.23 (m, 3H), 4.92-5.06 (m, 1H), 7.32 (d, 2H), 7.58 (d, 2H). MS m/z 402 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.13-1.26 (m, 3H), 1.43-1.60 (m, 1H), 1.64-1.85 (m, 1H), 1.95 (dt, 1H), 2.44-2.61 (m, 2H), 2.73-2.85 (m, 1H), 3.39 (s, 2H), 3.70 (s, 3H), 3.99-4.36 (m, 3H), 5.59 (br. s, 1H), 7.28 (d, 2H), 7.56 (d, 2H). MS m/z 402 (M+H)+

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