Hydrochloric Acid → Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

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Reaction Steps

2-(2-Chloro-4-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.13 g, 6.75 mmol) (reference compound 21) was dissolved in methyl THF (50 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.641 g, 10.12 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (2.067 g, 12.14 mmol) suspended in methyl THF (25 mL) and magnesium chloride (1.156 g, 12.14 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 15 h using an oversized stirring bar. The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.033 g, 6.07 mmol) suspended in methyl THF (25 mL) and magnesium chloride (0.578 g, 6.07 mmol) was added. The suspension was stirred at 50° C. for 15 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 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 2:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 63.6%) was isolated as a colorless oil. MS m/z 386 (M+H)+

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