5-Fluoronicotinic acid

Leete, E., G.B. Beden, and M.F. Manuel Fermentation of 5-fluoronicotine from 5-fluoronicotinic acid in Nicotiana tabacunr. Phytochemistry 10 (1971) 2687-2692. 

Anabasine.—5-Fluoronicotinic add [as (28)] is one of several unnatural substrates that have been metabolized by plants to alkaloid analogues cf. refs. 3 and 5. The major alkaloid of Nicotiana glauca is anabasine (33) it is essentially racemic. 5-Fluoronicotinic acid has been found recently to be converted into racemic 5-fluoroanabasine [as (33)] in this plant. ... 

Nicotine.—Nicotine (33) is assembled in Nicotiana species from nicotinic acid (31) and N-methyl-A -pyrroline (32). Administration to Nicotiana plants of 5-fluoronicotinic acid and derivatives of (32) methylated at C-2 and C-3 has resulted in the formation in vivo of unnatural nicotine analogues.In contrast, 4-methylnicotinic acid has been found not to be transformed in vivo into 4-methylnicotine, presumably because this particular methyl group interferes sterically with the appropriate enzyme reactions involved in nicotine biosynthesis. ... 

In the naphthyridine series, the same methodology was developed from 2,6-dichloro-5-fluoronicotinic acid prepared by an original route in 4 steps from 5-fluorouracil [14, 15]. 

The Balz-Schiemann reaction has been used for the preparation of the 4-iluoro-derivatives of pyridine and 2,5-, 2,6-, and 3,5-lutidine it has also been used to obtain 5-fluoronicotinic acid, required for conversion into the corresponding pyridylmethanol via LiAlH reduction of the ethyl ester. The introduction of F into fluoroaromatic compounds has been achieved via isotopic exchange in diazonium tetrafluoroborates. U.v. irradiation of aqueous solutions of the appropriate diazonium tetrafluoroborates has been used to procure the first ring-fluorinated imidazoks, e.g. photolysis of the diazonium solution obtained by adding sodium nitrite to 2-amino-imidazole in aqueous fluoroboric acid provides 2-fluoroimidazole contaminated with only a small amount of 2-azidoimidazole, the sole product of thermal decomposition of imidazole-2-diazonium tetrafluoroborate. 

Zhang Y, Stolle WT, Jian Z (2011) A modified approach to C-14-labeled 2-(3,4-difluorophenoxy)-5-fluoronicotinic acid and other halogen-substituted analogs. J Labelled Compd Rad 54 382-386... 

The ability of higher plants to carry out unnatural or aberrant syntheses is a relatively unexplored area of research. Some other examples are illustrated in Scheme 4. 5-Fluoronicotinic acid (12) is converted into 5-(luoronicotine (13) in the tobacco plant Nicotiana tabacum). Rapoport has found that methylated analogues of 1-methyl-l-pyrrolinium chloride yield methylated analogues... 

Fig. 5. Chemical structures of 2- and 6-[ F]fluoronicotinic acid diethylamide as well as 2- and 6-[ F]fluoronicotine.

At the beginning, we used NA as the inducer to the culture medium. However, the activity was not induced to achieve a high level production of 6-CHP. So we screened various nicotinic acid analogues such as 6-chloronicotinic acid, 6-fluoronicotinic acid, 2-chloronicotinic acid, 2-hydroxynicotinic acid, 2,6-dihydroxypyridine, 2,3-pyridinedicarboxylic acid, 3,4-pyridinedicarboxylic acid,... 

F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester 1/10/60-70 One-step synthesis Olberg etal. (2010)... 

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. 

The earliest examples of such fluorine-18 labelling are 2- and 6-[ F]fluoronico-tinic acid diethylamide and 2- and 6-[ F]fluoronicotine (Fig. 5). All were obtained in up to 40-50% radiochemical yield from the corresponding 2- and 6-chloro-(or bromo-) pyridine derivatives and [ F]fluoride as its cesium salt, in melted acetamide or DMSO at about 200 °C for 30 min [226-229]. 

In addition to the unnatural nicotine precursors mentioned above, 5-fluoro-nicotinic acid has been administered, initially with fatal consequences, to Nicoti-ana N. tabacum). The plants were able to adapt to small doses of the substrate, however, and the fluoronicotine (147) was produced. 

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