Phosphorus oxychloride → 8-Chloro-1,7-naphthyridine-3-carbonitrile

Temperature

110 °C

A screw-cap vial was charged with 3-chloro-1,7-naphthyridin-8(7H)-one (100 mg, 0.554 mmol), zinc cyanide (52.7 μl, 0.831 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (45.5 mg, 0.111 mmol), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg, 0.044 mmol), DMF (2.74 mL) and water (28 μL). The vial was purged with argon, sealed, and stirred at 110° C. for 1 hour. The mixture was filtered through a pad of Celite, which was rinsed with methanol and dimethylsulfoxide. The combined filtrates were concentrated, and a few drops of water were added. The resulting solids were collected by vacuum filtration, rinsed with water and dried. The solids were suspended in toluene (3.5 mL), and phosphorus oxychloride (98 μL, 1.052 mmol) and DIPEA (122 μL, 0.701 mmol) were added. The reaction was stirred at 120° C. for 1.5 hours, cooled to RT, diluted with EtOAc, and washed with 2 M aqueous sodium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with 5-50% EtOAc in heptanes, to provide the title compound (50 mg, 0.264 mmol) as a white solid. LC/MS (ESI+) m/z=190 (M+H)+.

1. customThe vial was purged with argon
2. customsealed
3. filtrationThe mixture was filtered through a pad of Celite, which
4. washwas rinsed with methanol and dimethylsulfoxide
5. concentrationThe combined filtrates were concentrated
6. additiona few drops of water were added
7. filtrationThe resulting solids were collected by vacuum filtration
8. washrinsed with water
9. customdried
10. stirringThe reaction was stirred at 120° C. for 1.5 hours
11. temperaturecooled to RT
12. washwashed with 2 M aqueous sodium carbonate
13. dry with materialThe organic portion was dried over anhydrous sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated
16. customThe crude material was purified by silica gel chromatography
17. washeluting with 5-50% EtOAc in heptanes

ORD record

ord-5141fefa80e54c4cb7b1a05d6298bc28

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09085576B2