2,6-naphthyridin-1(2H)-one

Synthesis

General procedure for the preparation of 2,6-naphthyridin-1(2H)-one: to a suspension of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (5 g, 28.9 mmol) in ethanol (50 mL) was added dropwise over a period of 20 minutes 49 mL of HBr (48% aqueous solution). The reaction mixture was heated to reflux and kept for 19 h, followed by cooling to room temperature. During cooling, formation of fine yellow crystals was observed. The mixture was cooled in a refrigerator for 1.5 h. The crystals were subsequently collected by filtration and washed with ether. Saturated aqueous NaHCO3 solution was carefully added to the yellow solid until gas release ceased. The off-white solid formed was collected by filtration and washed with water to give 1.83 g of the target product. The mother liquor from the two filtrations was combined and concentrated under reduced pressure. The residue was neutralized with saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. The residue was diluted with 300 mL of dichloromethane and 300 mL of methanol and the mixture was heated to reflux with a heat gun. After filtration to remove insoluble material, the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGEfast chromatography using a gradient elution with a dichloromethane solution of 0-6.5% methanol. The target product (0.96 g) was isolated as an off-white solid. The two batches of product were combined to give 2,6-naphthyridin-1(2H)-one (2.79 g, 19.1 mmol, 66% yield).LC/MS analysis: m/z 147.04 (M + H)+, retention time 1.407 min (Method 1).1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br.s, 1H). 9.07 (s, 1H), 8.62 (d, J = 5.49 Hz, 1H), 7.98 (d, J = 5.49 Hz, 1H), 7.33 (d, J = 7.02 Hz, 1H), 6.67 (d, J = 7.02 Hz, 1H).

References

[1] Patent: WO2009/158396, 2009, A1. Location in patent: Page/Page column 83-84
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3559 - 3572