1- Hydroxy-2,7-naphthyridine

Thiazolo[2,3 -/][ 1,6]naphthyridin-4-ium, anhydro-3,8-dicarboxy-6-hydroxy-X-ray, 6, 669 (76JA299)... 

In all the examples studied, the difference in the free energy between the anhydrous and hydrated species is 4 kcal/mole or less. ° Both electron deficiency and resonance stabilization are necessary for covalent hydration to be measurable. The necessity for electron deficiency is clearly shown in the following examples. The cation of 1,4,5-triazanaphthalene is anhydrous, but the cation of 1,4,5,8-tetraazanaphthalene is predominantly hydrated. 1,6-Naphthyridine cation is anhydrous, whereas the cations of the 3- and 8-nitro derivatives are predominantly hydrated. Also, the percentages of the hydrated form in the neutral species of 2-hydroxy-1,3-diaza-, 1,3,8-... 

Reaction of 2,4-dichloro-l,5-naphthyridine with ammonia (170°, 20 hr), hydrazine (100°, 16 hr), or aqueous hydrochloric acid (100°, 3 hr) was shown to yield the 2-amino- (47% yield) and 2-hydroxy-4-chloro derivatives (66% yield), but 2-hydrazino substitution (68% yield) was assumed. Disubstitution with ammonia (190°, 4 hr), hydrazine (100°, 48 hr), and ammonia-phenol (180°, 6 hr) occurred in high yield. Displacement of the 4-oxo group in 2,4-dioxo-l,5-naphthyridine occurs with aniline plus its hydrochloride (180°, 12 hr, 88% yield) to yield 429. Oxo groups in the 2- or 4-positions were... 

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315]. It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

Tlie presence of one or more electron-donating groups, such as the hydroxy substituent, is required to make easy nitration of the naphthyridines... 

Many reports deal with the preparation of numerous hydroxynitronaph-thyridones and nitronaphthyridinediones. By the nitration of 4-hydroxy-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) (51a-51d) using nitric acid in acetic acid, the corresponding 3-nitro substituted compounds (52a-52d) were obtained in reasonable-to-good yield (75JMC726 77MI1 96MI1). 

Treatment of 4-hydroxy-l-phenyl-l,8-naphthyridin-2-(lH)-one (76) with sodium nitrite gave the 3-nitroso derivative (77), which could be oxidized to 4-hydroxy-3-nitro-l-phenyl-l,8-naphthyridin-2(lH)-one (30a) (94SC3289). According to the authors, this method of preparing (30a) is more convenient for large-scale preparation than the one using A-phenyl-3-azaisatoic anhydride as starting material (see Section II,A,4,a) [(29a) (30a)]. 

Wlien more than one oxo (hydroxy) group is present, a mixture of ehloro-hydroxy- and diehloro-naphthyridines is usually formed. Tlius, reflux of 3-nitro-l,8-naphthyridin-2,7(lH,8H)-dione (114) with phosphorus oxy-ehloride gives the three halogeno eompounds (115,116, and 117), the ratio being dependent on the reaetion time (94EJMC735). 

A number of 1-substituted 4-chloro-3-nitro-l,8-naphthyridin-2(lH)-ones (122) (R are the same substituents as in the scheme in Section II,A,4,a) were obtained from the corresponding 4-hydroxy-l,8-naphthyridin-2(lH)-ones (30) (91JHC2029,91MI2 92JMC4866). 

Nitro-7-phenyl-l,8-naphthyridin-2(lH)-one 2-Chloro-3-nitro-l,8-naphthyridin-7(8H)-one 7-Chloro-3-nitro-l,8-naphthyridin-2(lH)-one 7-Chloro-4-hydroxy-3-nitro-l,5-naphthyridin-... 

Whereas FVT of 3-methyl derivative of 131 at 700-830 °C (10 " mbar) afforded 1,3-dimethyl-4-hydroxy-1,2-dihydro-1,8-naphthyridin-2-one, FVT... 

Chemical Name 6-[ [ [ [(4-Hydroxy-1,5-naphthyridin-3-yl)carbonyl] amino] -phenyl acetyl] -amino] -3,3-dimethyl-7-oxo4-thia-1 -atabicydo[3.2.0] -heptane-2-carboxylic acid... 

Common Name D-a-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)benzy penicillin... 

I n the above procedure, the use of 4-hydroxy-1,5-naphthyridine-3-carbonyl chloride in place of 4-hydroxy-1,5-naphthyridine-3-carboxyllc acid N-succinimide ester can also afford the same objective compound as above. The use of sodium thio-n-propoxide in place of sodium thiophenoxide can also give the objective compound in the form of the sodium salt. 

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