反应详情

温度

50 °C

Ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (3.00 g, 14.2 mmol) was dissolved in methanol (20 mL) and treated with K2CO3 (1.95 g, 14.2 mmol) in a minimum of water to de-salt. Reaction mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and 4-oxoazepane-1-carboxylic acid ethyl ester (2.62 g, 14.2 mmol) were dissolved in methanol (50 mL) and zinc chloride (7.23 g, 56.7 mmol) was added. The reaction mixture was stirred at 50° C., under a nitrogen atmosphere, for 2 h then cooled to rt. NaCNBH4 (1.78 g, 28.4 mmol) was added and the reaction mixture was stirred at 50° C. overnight under nitrogen. The reaction mixture was cooled to rt and the solvents were removed in vacuo, the residue was diluted with DCM and treated with sat. NaHCO3 sol., the resulting heterogeneous mixture was filtered through a celite pad and the filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl 4-[4-fluoro-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.26 g, 46%) as a colourless oil.

1. customReaction mixture
2. concentrationwas concentrated in vacuo
3. customazeotroped to dryness with toluene
4. temperaturethen cooled to rt
5. additionNaCNBH4 (1.78 g, 28.4 mmol) was added
6. stirringthe reaction mixture was stirred at 50° C. overnight under nitrogen
7. temperatureThe reaction mixture was cooled to rt
8. customthe solvents were removed in vacuo
9. additionthe residue was diluted with DCM
10. additiontreated with sat. NaHCO3 sol.
11. filtrationthe resulting heterogeneous mixture was filtered through a celite pad
12. washthe filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol.
13. dry with materialdried over MgSO4
14. customThe solvents were removed in vacuo
15. customthe residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 0% to 4% MeOH in DCM])