7- Amino-2-hydroxy-1,8-naphthyridines

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). 

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... 

Amino-6-phenyl-7-hydroxy-l,8-naphthyridine reacted with an excess of diethyl alkoxymethylenemalonates in the presence of concentrated hydrochloric acid or in acetic acid to afford JV-(l,8-naphthyridin-2-yl)aminomethylenemalonate (78) in 44-63% yields (69G677). 

The hydrolysis of diethyl N-(6-phenyl-7-hydroxy-1,8-naphthyridin-2-yl)aminomethylenemalonate in aqueous sodium hydroxide afforded 2-amino-6-phenyl-7-hydroxy-l, 8-naphthyridine (69G677). 

JAP624149) and a wide variety of l-lV-alkylperhydro-l,7-naphthyridines (207) have been obtained by reaction of the ether (208) with various alkylamines (66KGS427). A convenient synthesis of 5-hydroxy-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridine (211) starts from the 3-substituted amino isonicotinaldehyde (209) which undergoes a Wittig reaction followed by reduction to give (210), a compound that cyclizes readily in acid solution to (211) (82CPB1257). 

The Friedlander condensation of 2,6-diaminopyridine-3,5-dicarbaldehyde (393) with various ketones has been reported (77JOC3410). Reaction of the aldehyde with acetophenone, with deoxybenzoin and with a-tetralone generates the 5,10-dihydro-l,9,10-anthyridine derivatives (394 R = H), (394 R = Ph) and (395) respectively, whilst with acenaphthenone the nonacyclic anthyridine (396) is obtained. The condensation between 2-amino-3-ethoxy-carbonyI-l,8-naphthyridine (225) and alkyl carboxylates under basic conditions produces 4-hydroxy-1,9,10-anthyridin-2-ones (397) (79BAP571). 

The novel X-ray crystal structures of the following have all been reported 5-amino-4-(4-methoxyphenyl)-2-phenyl-7-(pyrrolidin-l-yl)-[l,6]naphthyridine-8-carbonitrile <1999AXC1670>, 5-amino-4-(4-diethylaminophenyl)-2-(4-hydroxy-phenyl)-7-(pyrrolidin-l -yl) [ 1,6]naphthyridine-8-carbonitrile <2001 AXC726>, 5-amino-4-(4-diethylaminophenyl)-2-phenyl-7-(pyrrolidin-l-yl)[l,6]naphthyridine-8-carbonitrile <2000AXC80>, and rotenone a-oxime <2003AXC392>. 

When the blocking group is other than a halogen atom or a keto group, only tars are formed. 8-Hydroxy- 1,7-naphthyridine61 is obtained from 3-amino-2-hydroxypyridine, and 1,5-naphthyridine is obtained from the 2-halo-3-aminopyridines when they are subjected to the Skraup reaction. 3-Aminopyridine 1-oxide aifords the parent 1,5-naphthyridine,62 and both 3-amino-6-hydroxypyridine and 3-amino-6-chloropyridine give 2-hydroxy-l,5-naphthyridine.63 Hart64 has applied the Skraup synthesis to 3-amino-4-hydroxypyridine and has obtained the expected 4-hydroxy-l,5-naphthyridine. 

Okuda condensed 4-amino-2,6-lutidine with EMME and converted the resulting hydroxy ester into 5,7-dimethyl-l,6-naphthyridine.86... 

Ferrarini et al. studied the reaction of 2,6-diamino- and 2-amino-6-acetamidopyridine with different jS-oxo esters in polyphosphoric acid at 80°C (90JHC881). Generally, complex reaction mixtures that contained different bi- and tricyclic products were obtained (see Scheme 7 and Table IX). The products were separated by flash chromatography. In the case of 2-amino-6-acetamidopyridine, the 2,6-diacetamidopyridine 97 was the main product. This compound 97 was also obtained by transamidation in good yield when 2-amino-6-acetamidopyridine was heated in polyphosphoric acid at 80°C. 2-Hydroxy-1,8-naphthyridines 98 were formed in a Conrad-Limpach-type cyclocondensation of 2-aminopyridines and /3-keto ester, while 4-hydroxy-1,8-naphthyridines 99 were probably formed by a ring transformation of 4//-pyrido[l,2-a]pyrimidin-4-ones 100 obtained by the cyclocondensation of 2-aminopyridines and a /3-keto ester. The cyclocondensation of 7-amino-4-hydroxy-l,8-naphthyridine 99 (R = H) and a... 

The cyclization of [(6-ethoxycarbonyl-2-pyridyl)amino]malonate 138 in Dowtherm A for 0.5 hour gave 48% 4-oxo-4//-pyrido[l,2-a]pyrimidine-3,6-dicarboxylate 139 and 6.8% 4-hydroxy-l,8-naphthyridine-3,7-dicarboxylate 140 (85JHC481). 

The analysis of these non-pairwise effects allowed us to estimate that the repulsive secondary interactions are twice as large as the attractive ones (+9 vs. -4 kJ mol ). This model has been used to rationalize the case of 2-oxo-7-hydroxy-l,3-dihydro- l //- 1,8-naphthyridine, a compound existing in the solid state probably as the 101 dimer with four intermolecular HBs and having the possibility to sustain SSPT. Unfortunately, the amide derivatives do not exist as amino/imino tautomers but as the diamino (diacylamino) tautomers and, therefore, cannot present the four HBs necessary for SSPT. We have extended these studies to other difunctional naphthyridines [114],... 

Hydroxy-2-methyl-3-phenylpropyl)amino]pyridine (24) underwent dehy-drative cyclization to give 3-methyl-4-phenyl-l,2,3,4-tetrahydro-l,5-naphthyridine (25) (70% H2S04, 0°C —>25°C, 15h 65%) that was easily dehydrogenated to give 3-methyl-4-phenyl-l,5-naphthyridine (26) (neat substrate, Pd/C, 200°C, 3 h 56%).879 Also other examples.48 485 865 967 1232 1245... 

Ethyl 4-amino-3-pyridinecarboxylate (90) in ethyl acetate gave 4-hydroxy-1,6-naphthyridin-2(l//)-one (91) (NaH, mineral oil, 20°C AcOEt], then 100°C, 2h %) 312 analogs somewhat similarly.312,996... 

Amino-6-hydroxy-2(l//)-pyridinone (113) with l-benoyl-2-dimethylami-noethylene gave 4-phenyl-1,6-naphthyridine-5,7(l//,6//)-dione (114) (reactants, AcOH, reflux, 5 min 95%) 757 analogs likewise.469,757,1310... 

Methyl-2-pyridinamine (45, R=Me) with diethyl (l-ethoxyethylidene)malo-nate gave ethyl 2,7-dimethyl-4-oxo-1,4-dihydro-l,8-naphthyridine-3-carbox-ylate (46) (Dowtherm, 240°C 22%) 249 2-pyridinamine (45, R H) with diethyl malonate gave 4-hydroxy-l,8-naphthyridin-2(lfl)-one (47) (neat reactants, heat 85 %) 693 and 2,6-pyridinediamine (45, R=NH2) with malic acid gave 7-amino-1,8-naphthyridin-2(l//)-one (48) (H2SO4, heat 85-97%) 389>681>1018... 

Amino-8-hydroxy-5-methyl-7-oxo-7,8-dihydro-l,8-naphthyridine-3-carboxylic acid (28, R = OH) (a tautomer of the 8-oxide) underwent reduction to 2-amino-5-methyl-7-oxo-7,8-dihydro-l,8-naphthyridine-3-carboxylic acid (28, R=H) (TiCl3, HC1, H20, 20°C -75%).748... 

A mi no-6-oxo-l-phenyl-4-(iV-phenylcarbamoyl methyl)-1,6-dihydro-3-pyridi-necarbonitrile (15) underwent thermal cyclization to l-amino-6-hydroxy-8-imino-2,7-dipthenyl-2,3,7,8-tetrahydro-2,7-naphthyridin-3(2//)-one (16) (Et3N, Me2NCHO, reflux 60%) also somewhat similar cyclizations.802... 

Amino-8-hydroxy-5-methyl-7-oxo-7, 8-dihydro-1,8-naphthyridine-3-carboxylic acid >320 748... 

Amino-8-hydroxy-7-oxo-7,8-dihdyro-l, 8-naphthyridine-3-carboxylic acid >320, IR 741... 

Methyl 7-acetamido-4-oxo-1,4-dihydro-1,8-naphthyridine-2-carboxylate Methyl l-acetyl-4-hydroxy-2-oxo-l,2-dihydro-1,8-naphthyridine-3-carboxylate Methyl 2-amino-5,7-dimethyl-1,8-naphthyridine-... 

CN [2S-[2a,5a,6p(S )]]-6-[[[[(4-hydroxy-l,5-naphthyridin-3-yl)carbonyllamino]phcnylacetyl]amino 1-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptanc-2-carboxylic acid... 

Berninamycinic acid is one of the products from acid hydrolysis of the cyclic peptide antibiotic berninamycin A, which is a potent inhibitor of bacterial protein synthesis. Berninamycinic acid has been assigned the structure (524), anhydro-3,8-dicarboxy-6-hydroxythiazolo[2,3-/][l,6]naphthyridin-4-ium hydroxide. The 6-hydroxy group arises during hydrolysis from a peptide-bonded amino group (77JA1645). 

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