2.6- Dichloro-1,5-naphthyridine synthesis

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

Dichloro-l,5-naphthyridine (54) and 2,7-dichloro-l,8-naphthyridine (55) have been used in the synthesis of macrocycles. Thus, reaction of heterocycle (54) with hexaethylene glycol and sodium hydride gives the 1 1 adduct (56) (60% yield) together with the 2 2 adduct (57) (2% yield). Heterocycle (55) similarly yields a 1 1 adduct (58) (30% yield) and a 2 2 adduct (59) (2% yield) <81JOC833>. 

The reaction of enaminones with 2-chloronicotinoyl chloride 95 or 2,6-dichloro-5-fluoronicotinoyl chloride mainly leads to N-acylation products that cyclize directly or on reacting with sodium hydride to form 8-acyl-7-alkyl-l,6-naphrhyridin-5(6//)-ones. Owing to their easy availability, these compounds are attractive precursors for the synthesis of polycondensed heterocycles like naphtha[3,4-//][l,6]naphthyridin-5-ones and pyrido[3,2-c][l,6]naphthyridine (2002T8543). 

Among procedures for the synthesis of 1,7-naphthyridines, four-component condensation of l-benzyl-3-hydroxy-5-piperidone 101 with 2,3-dichloro-6-fluorobenz-aldehyde, acetoacetic esters and ammonium acetate giving rise to 1,4,5,6,7-hexahydro-l,7-naphtyridin-5-one-3-carboxylic esters 102 attracts attention due to its simplicity. The compounds 102 and their N-debenzylation products 103 exhibit hypotensive activity (1985USP4596873, 1985USP4618678). 

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