Hydrochloric Acid → HCID 66732173, compound

Participants

Reaction Steps

2-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.07 g, 8.8 mmol) (reference compound 33) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.140 g, 13.20 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 (2.70 g, 15.84 mmol) suspended in methyl THF (30 mL) and magnesium chloride (1.508 g, 15.84 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 22 h using an oversized stirring bar (flask 2). The contents of flask 1 was transferred into 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 (1.348 g, 7.92 mmol) suspended in methyl THF (30 mL) and magnesium chloride (0.754 g, 7.92 mmol) was added. The suspension was stirred at 50° C. for 5 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 (5:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). The product methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.190 g, 59.3%) was isolated as a colorless oil. MS m/z 420 (M+H)+

Provenance & Evidence