反应详情

2-(3-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.112 g, 24.08 mmol) (reference compound 44) was dissolved in methyl THF (150 mL) and di(1H-imidazol-1-yl)methanone (5.86 g, 36.13 mmol) added. The suspension was stirred at room temperature under nitrogen for 3.5 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (7.38 g, 43.35 mmol) was suspended in methyl THF (150 mL) and magnesium chloride (4.13 g, 43.35 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h (flask 2). The orange suspension in flask 1 was now added to the white suspension in flask 2. The resulting yellow suspension was stirred under nitrogen at room temperature for 3 days. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE added. The phases were separated and the organic phase extracted with water, satd NaHCO3 and water. Evaporated the solvents to yield an orange oil. 42% of the oil was purified on Biotage (20%=>50% EtOAc in heptane, 6 CV+50%, 4 CV; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (664 mg, 18%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.8 g, 49%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20 (t, 3H), 1.56-1.93 (m, 4H), 2.62-2.73 (m, 2H), 2.83-3.03 (m, 2H), 3.41 (s, 2H), 3.59 (s, 3H), 3.83-3.93 (m, 1H), 4.07-4.20 (m, 3H), 6.82-6.93 (m, 3H), 7.15-7.22 (m, 1H). MS m/z 366 (M+H)+. Trans-isomer: MS m/z 366 (M+H)+

1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h (flask 2)
2. additionThe orange suspension in flask 1 was now added to the white suspension in flask 2
3. stirringThe resulting yellow suspension was stirred under nitrogen at room temperature for 3 days
4. additionadded
5. customThe phases were separated
6. extractionthe organic phase extracted with water
7. customEvaporated the solvents
8. customto yield an orange oil
9. custom42% of the oil was purified on Biotage (20%=>50% EtOAc in heptane, 6 CV+50%, 4 CV; Biotage® KP-SIL 340 g column)