60% |
With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 4.5h; |
Intermediate 37A: Diethyl 2-(3-fluoropyridin-2-yl)malonate A mixture of <strong>[1513-66-2]2,3-<strong>[1513-66-2]difluoropyridine</strong></strong> (2.00 g, 17.4 mmol), Cs2CO3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100 C. for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60% yield). 1H NMR (400 MHz, chloroform-d) delta 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H). |
60% |
With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 4.5h; |
A mixture of <strong>[1513-66-2]2,3-<strong>[1513-66-2]difluoropyridine</strong></strong> (2.00 g, 17.4 mmol), Cs2C03 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100 C for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin- 2-yl)malonate as a pale colored oil (2.68 g, 60%> yield). XH NMR (400 MHz, chloroform- d) delta 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=l. l Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H). |
|
With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 3h; |
Reference Production Example 29 A mixture of 3.95 g of <strong>[1513-66-2]2,3-<strong>[1513-66-2]difluoropyridine</strong></strong>, 13.2 g of diethyl malonate, 38 ml of dimethyl sulfoxide and 26.85 g of cesium carbonate was stirred for 3 hours at 100C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 12.18 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.38 g of diethyl (3-fluoro-2-pyridyl) malonate. 1H-NMR (CDCl3, TMS) delta (ppm): 1.28 (6 H, t, J=7.2 Hz), 4.28 (4 H, q, J=7.2 Hz), 5.08 (1 H, s), 7.30 (1 H, m), 7.43 (1 H, m), 8.41 (1 H) |