反应详情

2-(4-Fluorophenethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.34 g, 14.03 mmol) (reference compound 41) was dissolved in methyl THF (100 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (3.41 g, 21.05 mmol) added. The suspension was stirred at room temperature for 4 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (4.30 g, 25.25 mmol) suspended in methyl THF (100 mL) and magnesium chloride (2.404 g, 25.25 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 4 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the mixture (white suspension) was stirred at room temperature for 19 h. In a new flask was potassium 3-ethoxy-3-oxopropanoate (4.30 g, 25.25 mmol) suspended in methyl THF (100 mL) and magnesium chloride (2.404 g, 25.25 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 4 h using an oversized stirring bar and subsequently added to the reaction mixture. The mixture was stirred at room temperature for another 16 h at room temperature. 0.1 M HCl and DCM was added, the phases separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns. Mobile phase 2:1 heptane:EtOAc over 4 CV, then gradient from 2:1->1:1 heptane:EtOAc over 6 CV. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (0.74 g, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (3.17 g, 60%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.24 (t, 3H), 1.50-2.11 (m, 6H), 2.48-2.65 (m, 2H), 2.67-7.77 (m, 1H), 3.03-3.14 (m, 1H), 3.50 (s, 2H), 3.69 (s, 3H), 3.84-3.93 (m, 1H), 4.07 (p, 1H), 4.12-4.22 (m, 2H), 6.95 (t, 2H), 7.08-7.16 (m, 2H). MS m/z 380 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.32 (m, 3H), 1.41-2.11 (m, 6H), 2.42-2.66 (m, 2H), 2.76-2.96 (m, 2H), 3.45 (s, 2H), 3.69 (s, 3H), 4.01-4.65 (m, 4H), 6.97 (t, 2H), 7.13 (s, br., 2H). MS m/z 380 (M+H)+

1. customIn a separate flask was
2. stirringThe suspension was stirred at 50° C. under nitrogen for 4 h
3. additionThe contents of flask 1 was added to flask 2
4. stirringthe mixture (white suspension) was stirred at room temperature for 19 h
5. customIn a new flask was
6. stirringThe suspension was stirred at 50° C. under nitrogen for 4 h
7. additionsubsequently added to the reaction mixture
8. stirringThe mixture was stirred at room temperature for another 16 h at room temperature
9. customthe phases separated
10. extractionthe aqueous phase was extracted with DCM
11. washThe combined organic layers were washed with satd NaHCO3
12. filtrationfiltered through a phase separator
13. customevaporated
14. customThe residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns