反应详情

2-(4-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.428 g, 14.99 mmol) (reference compound 43) was dissolved in methyl THF (100 mL) and di(1H-imidazol-1-yl)methanone (3.65 g, 22.49 mmol) added. The suspension was stirred at room temperature overnight under nitrogen (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.59 g, 26.99 mmol) was suspended in methyl THF (100 mL) and magnesium chloride (2.57 g, 26.99 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h (flask 2). The slightly yellow suspension in flask 1 was now added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. 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, sat NaHCO3 and water. Evaporated the solvents to yield a yellow oil. The diastereoisomers were separated on Biotage (0%=>70% EtOAc in heptane, 7 CV; Biotage® KP-SIL 340 g column). Mixed fractions were repurified on Biotage (30%=>65% EtOAc in heptane, 10 CV; Biotage® KP-SIL 50 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.458 g, 10.36%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (2.531 g, 57.3%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.25 (m, 3H), 1.61-1.68 (m, 1H), 1.77-1.91 (m, 3H), 2.64-2.73 (m, 2H), 2.82-2.87 (m, 1H), 2.94-3.00 (m, 1H), 3.43 (s, 2H), 3.60 (s, 3H), 3.90 (dd, 1H), 4.11-4.17 (m, 3H), 6.91-6.96 (m, 2H), 7.08-7.13 (m, 2H). MS m/z 366 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.15-1.26 (m, 3H), 1.39-1.94 (m, 4H), 2.59-3.00 (m, 4H), 3.32-3.66 (m, 5H), 3.96-4.28 (m, 3H), 4.50 (d, br., 1H), 6.88-6.95 (m, 2H), 6.99-7.18 (m, 2H). MS m/z 366 (M+H)+

1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h (flask 2)
2. additionThe slightly yellow suspension in flask 1 was now added to the white suspension in flask 2
3. stirringThe resulting white suspension was stirred under nitrogen at room temperature overnight
4. additionadded
5. customThe phases were separated
6. extractionthe organic phase extracted with water
7. customEvaporated the solvents
8. customto yield a yellow oil
9. customThe diastereoisomers were separated on Biotage (0%=>70% EtOAc in heptane, 7 CV; Biotage® KP-SIL 340 g column)
10. customMixed fractions were repurified on Biotage (30%=>65% EtOAc in heptane, 10 CV; Biotage® KP-SIL 50 g column)