Hydrochloric Acid → HCID 131730494, compound

Participants

Reaction Conditions

Reaction Steps

Magnesium chloride (2.3 g, 24.16 mmol) and potassium 3-ethoxy-3-oxopropanoate (4 g, 23.50 mmol) were suspended in methyl THF (70 mL) under nitrogen and the resulting suspension was stirred at 50° C. with an oversized stirring bar for 18 h, then cooled to room temperature (flask 1). To a suspension of 2-(3-fluoro-5-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.58 g, 12.61 mmol) (reference compound 58) in methyl THF (70.0 mL) was added di(1H-imidazol-1-yl)methanone (3.36 g, 20.72 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 72 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-5-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (758 mg, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.52 g, 46%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.28 (m, 3H), 1.64-1.95 (m, 4H), 2.68-2.81 (m, 2H), 2.95 (dd, 1H), 3.02 (ddd, 1H), 3.45 (s, 2H), 3.59 (s, 3H), 3.84-3.96 (m, 1H), 4.06-4.23 (m, 3H), 7.04-7.11 (m, 1H), 7.15 (d, 1H), 7.19-7.24 (m, 1H). MS m/z 434 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.29 (m, 3H), 1.43-1.99 (m, 4H), 2.75-2.89 (m, 1H), 2.89-3.04 (m, 3H), 3.36-3.72 (m, 5H), 4.03-4.33 (m, 3H), 4.49-4.72 (m, 1H), 6.98-7.20 (m, 2H), 7.20-7.28 (m, 1H).

Provenance & Evidence