Dimethylformamide → 5-Ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene

Phosphorus oxychloride (7.9 ml, 85 mmol) was added to dimethylformamide (17.04 ml, 220 mmol) dropwise under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then added dropwise under ice cooling to a solution of 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethanone (21.5 g (100 mmol), prepared as described in T. F. Gallagher et al., Bioorg. Med. Chem., 5, 49–64 (1997)) dissolved in a mixed solution of dimethylformamide (140 ml) and dichloromethane (280 ml). The resulting mixture was stirred at 50° C. for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, water was added, adjusted to pH 9 to 10 by adding an aqueous solution of 6 N sodium hydroxide and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml). To the resulting solution was added ethyl thioacetate (11 ml, 100 mmol), and then triethylamine (25 ml, 180 mmol) with stirring under ice cooling. The resulting mixture was stirred at room temperature for 1 hour, then 80° C. for 3 hours. The resulting mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3), to give the title compound (18.11 g) as a brown viscous oil (yield 55%).

1. stirringThe resulting mixture was stirred at 50° C. for 2 hours
2. temperatureAt the end of this time, the reaction mixture was cooled to room temperature
3. extractionextracted with dichloromethane
4. washThe organic layer was washed with water
5. dry with materialdried over anhydrous magnesium sulfate
6. customthe solvent was removed by distillation under reduced pressure
7. dissolutionThe residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml)
8. stirringThe resulting mixture was stirred at room temperature for 1 hour
9. wait80° C. for 3 hours
10. temperatureThe resulting mixture was cooled to room temperature
11. custompartitioned between water and dichloromethane
12. washThe organic layer was washed with water
13. dry with materialdried over anhydrous magnesium sulfate
14. customthe solvent was removed by distillation under reduced pressure
15. customThe residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3)

ORDレコード

ord-23a18566ce224943aeb1c23107d57dc5

出典データセット

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07091352B2