反应详情

温度

50 °C

A suspension of magnesium chloride (2.60 g, 27.33 mmol) and ethyl potassium malonate (4.65 g, 27.33 mmol) in dry THF (80 mL) was stirred under nitrogen atmosphere at 50° C. for 2.5 h (flask 1). In another flask di(1H-imidazol-1-yl)methanone (3.69 g, 22.77 mmol) was added portionwise to a solution of 2-(2-fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.483 g, 15.18 mmol) (reference compound 45) in dry THF (20 mL) at 0° C. under nitrogen atmosphere. The ice bath was removed and the solution was stirred for 2 h at room temperature (flask 2). The contents of flask 1 was added slowly to flask 2 and the resulting mixture was stirred for 19 h under nitrogen. The reaction mixture was concentrated and the residue was taken up in EtOAc and H2O. The aqueous phase was extracted once with EtOAc and the combined organic phases were washed with H2O, 10% Na2CO3 and then dried over Na2SO4. The compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, first 8:2 for 2 CV then linear gradient heptanes/ethyl acetate 8:2 to 3:7 over 7CV. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (3.19 g, 58%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.30 (m, 3H), 1.63-1.99 (m, 4H), 2.63-2.76 (m, 1H), 2.77-3.13 (m, 3H), 3.46 (s, 2H), 3.53 (s, 3H), 3.85-3.99 (m, 1H), 4.17 (q, 2H), 4.22-4.32 (m, 1H), 6.93-7.08 (m, 2H), 7.09-7.22 (m, 2H). MS m/z 366 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.32 (m, 3H), 1.39-1.99 (m, 4H), 2.52-3.12 (m, 4H), 3.37-3.71 (m, 5H), 4.18 (q, 2H), 4.02-4.32 (m, 1H), 4.48-4.71 (m, 1H), 6.94-7.24 (m, 4H). MS m/z 366 (M+H)+

1. customThe ice bath was removed
2. stirringthe solution was stirred for 2 h at room temperature (flask 2)
3. additionThe contents of flask 1 was added slowly to flask 2
4. stirringthe resulting mixture was stirred for 19 h under nitrogen
5. concentrationThe reaction mixture was concentrated
6. extractionThe aqueous phase was extracted once with EtOAc
7. washthe combined organic phases were washed with H2O, 10% Na2CO3
8. dry with materialdried over Na2SO4
9. customThe compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, first 8:2 for 2 CV