反应详情

温度

-78 °C

A dry 3-neck, 250-mL round bottom flask was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (3.0 g, 10.07 mmol), anhydrous THF (50.4 mL) and chloroiodomethane (0.878 mL, 12.09 mmol). The flask was fitted with a rubber septum and pressure-equalized dropping funnel topped with an inert gas inlet and placed under a nitrogen atmosphere. The mixture was cooled to −78° C. (CO2/acetone bath). Methyllithium (7.56 mL of a 1.6 M solution in Et2O, 12.09 mmol) was added dropwise to the mixture from the dropping funnel over 10 min. The mixture was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl (10 mL) and warmed to RT. The mixture was adjusted to a pH=6 and extracted with Et2O (3×75 mL). The extract was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using an 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (1.3 g, 4.30 mmol, 43% yield) as a pale orange solid. LC/MS [M+H]+=302. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.50 (1 H, s), 6.44 (1 H, s), 4.18 (2 H, s), 3.87 (3 H, s), 3.62-3.71 (2 H, m), 2.75-2.86 (3 H, m), 1.97 (2 H, s), 1.84 (2 H, s).

1. customThe flask was fitted with a rubber septum
2. customtopped with an inert gas inlet
3. customquenched with saturated NH4Cl (10 mL)
4. temperaturewarmed to RT
5. extractionextracted with Et2O (3×75 mL)
6. washThe extract was washed with brine
7. dry with materialdried (Na2SO4)
8. concentrationconcentrated on a rotary evaporator
9. customThe resultant residue was purified by flash chromatography
10. washan 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc
11. additionThe fractions containing the product
12. concentrationconcentrated on a rotary evaporator