A One-Pot Diazotation–Fluorodediazoniation Reaction and Fluorine Gas for the Production of Fluoronaphthyridines

Several synthetic routes to 7-fluoro-2-methoxy-8-methyl-1,5-naphthyridine (1) are presented, and their suitability for scale-up is discussed. The way of introducing the fluorine atom is crucial. Early routes start from commercially available fluorinated building blocks or employ F+ reagents like SelectFluor and delivered up to 70 kg of 7-fluoro-2-methoxy-1,5-naphthyridine (18). To prepare for larger scales, the focus turned to the use of HF or elemental fluorine, both one of the cheapest sources of fluorine. The first method, a one-pot diazotation–fluorodediazoniation with 6-methoxy-1,5-naphthyridin-3-amine (9) in HF gave the fluorinated naphthyridine 18 in high yield and purity without isolation of the unstable diazonium salt, the latter being a severe drawback of the related Balz–Schiemann protocol. The second method relies on the use of fluorine gas for a surprisingly selective ortho-fluorination of 6-methoxy-1,5-naphthyridin-4-ol (10).