反应详情

1-(Methoxycarbonyl)-2-(2,4,5-trifluorophenyl)piperidine-4-carboxylic acid (2.388 g, 7.53 mmol) (reference compound 27) was dissolved in methyl THF (50 mL) and di(1H-imidazol-1-yl)methanone (1.831 g, 11.29 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.306 g, 13.55 mmol) was suspended in methyl THF (50.0 mL) and magnesium chloride (1.290 g, 13.55 mmol) added. The suspension was stirred at 50° C. under nitrogen for 5.5 h using an oversized stirring bar (flask 2). The 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 overnight. 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 washed with water, satd NaHCO3 and water and was evaporated. Traces of water were azeotropically removed by MeCN to yield a yellow oil. The residue was purified on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.877 g, 64%) was isolated as colorless oil. 1H NMR (600 MHz, cdcl3) δ 1.19-1.29 (m, 3H), 1.49-2.19 (m, 3H), 2.22-2.29 (m, 1H), 2.82-2.91 (m, 1H), 3.34 (ddd, 1H), 3.39-3.48 (m, 2H), 3.62 (s, 3H), 4.05-4.20 (m, 3H), 5.00-5.06 (m, 1H), 6.85-7.00 (m, 2H). MS m/z 388 (M+H)+.

1. stirringThe suspension was stirred at 50° C. under nitrogen for 5.5 h
2. additionThe suspension in flask 1 was now added to the white suspension in flask 2
3. stirringThe resulting beige suspension was stirred under nitrogen at room temperature overnight
4. additionadded
5. customThe phases were separated
6. washthe organic phase washed with water
7. customwas evaporated
8. customTraces of water were azeotropically removed by MeCN
9. customto yield a yellow oil
10. customThe residue was purified on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column)