Dimethylformamide → 3-Chloro-3-(pyridin-4-yl)acrylonitrile

To ice-cooled DMF (32.1 mL, 0.400 mol) was added POCl3 (18.6 mL, 0.200 mol) dropwise with stirring over 1 h. After 30 min, the mixture was allowed to warm to room temperature. Then, 4-acetylpyridine (11.1 mL, 0.100 mol) was added dropwise over 2 h. DMF (50 mL) was added additionally and the mixture was maintained at room temperature with a water bath. Hydroxylamine hydrochloride (13.9 g, 200 mmol) was added portion wise over 2 h being careful to keep the reaction temperature under 80° C. DMF (50 mL) was added again and hydroxylamine hydrochloride (13.9 g, 200 mmol) was added portion wise over 30 min. Then, the mixture was heated at 80° C. After 1.5 h, the mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was cooled to 0° C., water (500 mL) was added, and the mixture was neutralized with sodium hydrogen carbonate. Water (500 mL) was added again to dissolve all, and the mixture was extracted with ethyl acetate (500 mL, 3×200 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, filtered and concentrated at reduced pressure. The black residue obtained was dissolved with ethyl acetate (300 mL) and the solution was filtered through a pad of silica gel (100 g). The silica gel was washed with ethyl acetate (1 L). The filtrate was concentrated at reduced pressure to give a gray solid. 1H NMR analysis indicated the purity was about 60%. This solid was triturated with dichloromethane (100 mL) and filtered. The filtrate was purified by column chromatography (120 g×2, silica, Combiflash, dichloromethane to 50:50 dichloromethane/ethyl acetate) to afford the title compound (5.97 g, 36%) as a white solid:

1. waitAfter 30 min
2. temperaturethe mixture was maintained at room temperature with a water bath
3. customunder 80° C
4. temperatureThen, the mixture was heated at 80° C
5. waitAfter 1.5 h
6. temperatureto cool to room temperature
7. stirringstirring
8. waitwas continued overnight
9. temperatureThe mixture was cooled to 0° C.
10. dissolutionto dissolve all, and the mixture
11. extractionwas extracted with ethyl acetate (500 mL, 3×200 mL)
12. washThe combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated at reduced pressure
16. customThe black residue obtained
17. filtrationthe solution was filtered through a pad of silica gel (100 g)
18. washThe silica gel was washed with ethyl acetate (1 L)
19. concentrationThe filtrate was concentrated at reduced pressure
20. customto give a gray solid
21. customThis solid was triturated with dichloromethane (100 mL)
22. filtrationfiltered
23. customThe filtrate was purified by column chromatography (120 g×2, silica, Combiflash, dichloromethane to 50:50 dichloromethane/ethyl acetate)

ORD record

ord-7e0a072570104a8caa6ab5900e1712ca

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08691828B2