反应详情

2-(3,4-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.62 g, 21.13 mmol) (reference compound 53) was dissolved in methyl THF (150 mL) and di(1H-imidazol-1-yl)methanone (5.14 g, 31.70 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 (6.47 g, 38.03 mmol) was suspended in methyl THF (150 mL) and magnesium chloride (3.62 g, 38.03 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h using an oversized stirring bar (flask 2). The yellow 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 4 h. 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 extracted with water, satd NaHCO3 and water. Evaporated the solvents to yield an orange oil. The diastereomers were separated in 2 runs on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.278 g, 3.4%) and cis-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.233 g, 27.6%) were isolated as yellow oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.21-1.29 (m, 3H), 1.61-1.98 (m, 4H), 2.63-2.78 (m, 2H), 2.82-3.11 (m, 2H), 3.47 (s, 2H), 3.64 (s, 3H), 3.86-3.97 (m, 1H), 4.12-4.23 (m, 3H), 6.85-6.92 (m, 1H), 6.95-7.13 (m, 2H). MS m/z 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.29 (m, 3H), 1.40-2.00 (m, 4H), 2.63-3.03 (m, 4H), 3.37-3.75 (m, 5H), 4.00-4.31 (m, 3H), 4.55 (d, br., 1H), 6.77-7.12 (m, 3H). MS m/z 384 (M+H)+

1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h
2. additionThe yellow 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 4 h
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. customThe diastereomers were separated in 2