Hydrochloric Acid → HCID 131730497, compound

Participants

Reaction Conditions

Reaction Steps

Magnesium chloride (3.25 g, 34.13 mmol) and potassium 3-ethoxy-3-oxopropanoate (5.82 g, 34.19 mmol) were suspended under a nitrogen atmosphere in methyl THF (100 mL) and stirred with an oversized stirring bar at 50° C. for 18 h, then cooled to room temperature (flask 1). To a suspension of 2-(3-fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.56 g, 18.06 mmol) (reference compound 59) in methyl THF (100 mL) was added di(1H-imidazol-1-yl)methanone (4.77 g, 29.42 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 2 h (flask 2). The contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). Resulting suspension stirred at room temperature for 18 h. 3.8 M HCl was added (ca. 200 mL) and the resulting biphasic mixture stirred vigorously for 30 min. MTBE was added and the phases separated. The organic phase was washed with water, satd NaHCO3 and water, then dried over MgSO4 and evaporated. The residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.794 g, 10%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)-benzyl)piperidine-1-carboxylate (3.57 g, 45%) were isolated as pale yellow oils. Cis-isomer: MS m/z 434 (M+H)+. Trans-isomer: MS m/z 434 (M+H)+

Provenance & Evidence