2- Chloro-3- -1,8-naphthyridine

Several 3-fiuoropyridine derivatives are employed to produce enoxacia, tosufioxacia, and other naphthyridine antibacterials (Table 14). Examples of such iatermediates iaclude 2,6-dichloro-5-fiuoronicotiQonitrile (429), ethyl 2,6-dichloro-5-fiuoronicotiQate (430), 2-chloro-3-fiuoropyridine (393), 6-acetyl-2-(4-acetyl-l-piperaziQyl)-3-fiuoropyridine (431), and 5-fiuoro-2,6-dihydroxynicotiQamide (394). 

A methiodide of 6-chloro-2-methyl-l,5-naphthyridine has been 2irepared no structure was assigned, but it is probably the 1-salt (142). The 5-N atom of 1,6-dimethyl-2-naphthyridone undergoes... 

The relation of activation by para vs. ortho ring-nitrogen in bicy-clics is altered by these special cases. For example, 4-chloroquinazoline (4-Cl-l,3-diaza) is much more reactive than the 2-chloro isomer (2-Cl-l,3-diaza) for two reasons, one being the poor activation in 2-Le-3-aza compounds. 4-Chloro-l,8-naphthyridine will be decreased in reactivity relative to its 2-chloro isomer due to the very poor activation in 4-Le-8-aza compounds and it may be only slightly more reactive than the mono-aza analog 4-chloroquinoline. The greater reactivity at the 2-position of 2,4-dichloro-l,8-naphthyri-dine 3 can be ascribed to this 4-Le-8-aza effect. ... 

Chloro-6-methyl-l,5-naphthyridine reacts readily with methano-lic methoxide (65°, 7 hr, 75% yield), but more vigorous conditions (180°, 2-7 hrs, 30-85% yield) were used for various aminations. The 4-chlorodiazanaphthalene reacted with a sec-alkylamine under less vigorous conditions (95%, 36 hr, 85% yield) and with ammonia-phenol (180°, 3 hr, 50% yield) gave the phenoxy derivative which was also alkylaminated (200°, 3 hr, 90% yield).The 3-bromo and 3-bromo-2-ethoxy derivatives of428 were aminated with copper sulfate and concentrated ammonia (170°, 40 hr, 75% yield). 

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... 

Nucleophilic chlorination of 1,5-naphthyridine mono- and di-N-oxides yields 2-chloro- and 2,6-dichloro-naphthyridines via electrophilic catalysis of the reaction of intermediates such as 430 with chloride ion. An interesting example of electrophilic catalysis is the... 

Methoxylation of l-chloro-3-methyl-2,7-naphthyridine occurs exothermically on addition to methanolic methoxide (20°). The 1-chloro or l-chloro-3-methyl derivatives are substituted with... 

Tile easy availability of (di)nitronaphthyridones, in which the lactam part can easily be converted into an iminochloride, has successfully led to preparation of the parent (di)nitronaphthyridines by removal of the chloro atom. For that purpose the chloro atom in the 2- and 4-chloro derivative of the 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (78a-78e) was first substituted with tosylhydrazine to give the corresponding tosyl-hydrazide, which then was hydrolyzed in alkaline solution into the corresponding 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (79a, 79b, and 79c). 

Attempts to obtain 5-nitro-l,7-naphthyridine and 3,6-dinitro-l,8-naph-thyridine (83) from the corresponding 8-chloro-5-nitro-l,7-naphthyridine and 2-chloro-3,6-dinitro-l,8-naphthyridine using the similar reaction failed (85JHC761 98MI2). However, 3,6-dinitro-l,8-naphthyridine (83) could be prepared in 21% yield by hydrazino-dechlorination of 2-chloro-3,6-dinitro-1,8-naphthyridine (82) and subsequent cupric sulfate oxidation of the intermediate 2-hydrazino-3,6-dinitro-l,8-naphthyridine (93LA471). 

In all 3-nitronaphthyridines with an unsubstituted C-2 position (84a, 84f, and 84j) no traces of the corresponding 2-amino-3-nitro-l,X-naphthyridines (X = 5, 6, and 8) were obtained. As already mentioned, in the aminations of 2-R-3-nitronaphthyridines where R is a chloro or ethoxy group, no amino-dechlorination or amino-deethoxylation was observed. 

The compounds 87a and 87b are aminated at position 4, yielding the 4-amino compound (88a, 40%) and the 2,4-diamino compound (88b, 11%) respectively the 2-ethoxy compound (87c), however, undergoes amination at position 4 as well at position 5, giving a mixture of the 4-amino compound (88c, 20%) and the 5-amino compound (89a, 14%).Tlie 2-chloro compound (87d) yields a highly complex reaction mixture from which the 5-amino compound (89b), the 2,4-diamino derivative (88b), and 2,5-diamino-l,8-naphthyridine (89c) could be isolated. l-Ethyl-3-nitro-l,8-naphthyridin-2(lH)-one (90a) and 3,6-dinitro-l-ethyl-l,8-naphthyridin-2(lH)-one (90b) were aminated exclusively in the 4-position to give compounds 91a (62%) and 91b (45%), respectively (93LA471). 

As discussed before, in liquid ammonia/potassium permanganate nucleo-phugal substituents at C-2, such as ones present in the naphthyridines (84c, 84e, 84h, 84i, 841, and 84m), could not be replaced by the amino group only SnH substitution takes place. However, it has been observed that in the reaction of the 2-chloro-3-nitro-l,8-naphthyridine (92c) with liquid methylamine/potassium permanganate S H substitution as well as methylamino-dechlorination takes place, yielding 2,4-bis-(methylamino)-3-nitro-l,8-naphthyridine (93c). 

Using the same methodology, a number of 3,6-dinitro-l,8-naphthyridines (87a-87g) were converted with the LMA/PP system into the methylamino products (94). Tire methylamino group usually enters at position 4, but in cases where a chloro or methoxy substituent is present at C-2, 2,4-bis(methylamino) derivatives were isolated (97MI3). 

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

Analogously, 4-chloro-8-iiitro-l,6-iiaphthyridiiie (80, 68%) (63JCS4237), 8-chloro-5-iiitro-l,7-iiaphthyridiiie (97, 51%) (78JHC731), and 2-chloro-3,6-dinitro-l,8-naphthyridine (82, 66%) (85JHC761) were obtained from 8-nitro-l,6-naphthyridine-4(lH)-one, 5-nitro-l,7-naphthyridin-8(7H)-one, and 3,6-dinitro-l,8-naphthyridin-2(lH)-one, respeetively. 

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). 

Catalytic hydrogenation (Pd/C) of 2-chloro-3-nitro-l,5-naphthyridine (125, R = Cl) in methanolic solution afforded 3-amino-l,5-naphthyridine (126, R = H, 74%) isolated in the form of its trihydrochloride (40MI1). Similar Pd/C hydrogenation of 2-ethoxy-3-nitro-l,5-naphthyridine (125, R = OEt) gave 3-amino-2-ethoxy-l,5-naphthyridine (126, R = OEt, 47%) (80RTC83). Reduction with tin(II) chloride in hydrochloric acid also leads to 126, (R = OEt, 73%) (63RTC997). 

Interestingly, no dehalogenation occurs when 2-chloro-3-nitro-l,8-naph-thyridine (127) is treated with tin(II) chloride in hydrochloric acid 3-amino-2-chloro-l,8-naphthyridine (128,33%) is the sole product (76S691). 

Tin(II) chloride reduction of both 4-chloro-3-nitro-l,8-naphthyridine (129, R = Cl) (79PJC1665) and 3-nitro-l,8-naphthyridine (129, R = H) (76S691) gave in 30-35% yield 3-amino-l,8-naphthyridine (130, R = H) reduction of the 4-amino-3-nitro compound (129, R = NH2) yielded 3,4-diamino-l,8-naphthyridine (130, R = NH2,37%) (79PJC1665). 

Subjecting 8-chloro-5-iiitro-l,7-iiaphthyridiiie (97) to reduction with tin(II) chloride leads, besides loss of the chloro atom and reduction of the nitro group, i.e., formation of 5-amino-l,7-naphthyridine (131, 22%), to the formation of small amounts of 5-amino-6,8-dichloro- (132, 1.5%) and 5-amino-6-(or 8-)chloro-l,7-naphthyridine (133, 2.5%) (88PJC305). 

Deuterio-3-iiitro-l,6-iiaphthyridiiie (168) was prepared from 4-chloro-3-iiitro-l,6-iiaphthyridiiie (166) by a reaction with tosyl hydrazide and subsequent hydrolysis of the 4-tosylhydrazino derivative (167) with Na2C03/ D2O solution (83RTC359). 7-Deuterio-l,8-naphthyridin-2(lH)-one was prepared by heating l,8-naphthyridin-2(lH)-one with deuterium oxide at 230°C for 35 h (85JHC761). Tliis deuterio compound could be converted into 2-chloro-(or 2-ethoxy-) 7-deuterio-3,6-dinitro-l,8-naphthyridine. 

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