反应详情

A mixture of [1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid (2 g, 9.24 mmol), potassium carbonate (1.54 g, 11.1 mmol) and methyl iodide (2.89 mL, 46.5 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with dichloromethane (x2). The combined organic layers were washed with saturated sodium hydrogencarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) added. The reaction was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was dissolved in N,N-dimethylformamide (30 mL). 2,4-Difluorophenethyl bromide (2.26 g, 10.2 mmol) and potassium carbonate (5.14 g, 37.2 mmol) were added and the reaction heated at 60° C. overnight. The cooled reaction mixture was diluted with water and extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% methanol/dichloromethane, to give methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetate (1.3 g, 52%). 1H NMR (360 MHz, CDCl3) δ 7.15–7.09 (1H, m), 6.79–6.71 (2H, m), 3.64 (3H, s), 3.48–3.44 (2H, m), 2.87–2.75 (3H, m), 2.60 (4H, s), 2.57 (2H, d, J=7.1 Hz); m/z (ES+) 270 (M+H)+.

1. extractionextracted with dichloromethane (x2)
2. washThe combined organic layers were washed with saturated sodium hydrogencarbonate solution
3. dry with materialdried over MgSO4
4. concentrationconcentrated in vacuo
5. dissolutionThe residue was dissolved in dichloromethane (5 mL)
6. additiontrifluoroacetic acid (5 mL) added
7. stirringThe reaction was stirred at room temperature for 30 minutes
8. customThe solvent was removed in vacuo
9. dissolutionThe residue was dissolved in N,N-dimethylformamide (30 mL)
10. temperaturethe reaction heated at 60° C. overnight
11. customThe cooled reaction mixture
12. extractionextracted with dichloromethane (x3)
13. washThe combined organic layers were washed with brine
14. dry with materialdried over MgSO4
15. concentrationconcentrated in vacuo
16. customThe residue was purified by flash column chromatography on silica
17. washeluting with 5% methanol/dichloromethane