1.8- Naphthyridine-3-carboxylates 4-hydroxy

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... 

CsH, N02 103003-01-6) see Indeloxacine ( )-2-(hydroxymethyl)morphoIine see under 2-hydroxymethylmorpholine 4-hydroxy-7-methyl-l,8-naphthyridine-3-carboxylic acid (C,()HhN20 i 13250-97-0) see Nalidixic acid 4-hydroxy-7 melhyM,8-naphthyridine-3-carboxyIic acid ethyl ester... 

When 3-aminopyridine was reacted with EMME in Dowtherm A, first at 150°C for 1 hr and then at boiling temperature for 1 hr, ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate was obtained in 73-82% yields (46JA-1317). 

When position 2 of the pyridine moiety of 3-pyridylaminomethylene-malonates (983) was substituted, the thermal ring closure occurred in position 4 to yield 4-hydroxy-l,7-naphthyridine-3-carboxylates (984) (66BRP1022214 69USP3429887 70BRP1182369, 70USP3506668, 70USP 3517014 84EUPI15469). 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

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). 

Hydroxy-l,5-naphthyridine-3-carboxylic acid N-succinimide ester Sodium bicarbonate Sodium thiophenoxide Triethylamine... 

In the above procedure, the use of 4-hydroxy-l,5-naphthyridine-3-carbonyl chloride in place of 4-hydroxy-l,5-naphthyridine-3-carboxylic 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. 

Ethyl 5-cyano-2-(a-cyanoethoxycarbonylmethyl)-4-oxo-l,4-dihydro-3-pyridine-carboxylate (42) gave ethyl 3-cyano-7-hydroxy-4,5-dioxo-1,4,5,6-tetrahydro-l,6-naphthyridine-8-carboxylate (43) (Et3N, EtOH, reflux, 3 h 65%).698... 

Carboxy-6-hydroxythiazolo[2,3-/ [ 1,6]-naphthyridin-4-ium-3-carboxylate (152) (beminamycinic acid) underwent exhaustive methylation to afford methyl 8-methoxy-6-(l-methoxycarbonyl-2-methylthiovinyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylate (153) (Mel, Ag20 low yield)293 or hydrogenolysis to furnish a separable mixture of 6-(l-carboxylatoethyl)-8-hydroxy-l,2,3,4-tetrahydro-l,6-naphthyridin-6-ium-2-carboxylic acid (154) and 8-hydroxy-1,2,3,4-tetrahydro-l,6-naphthyridine-2-carboxylic acid (155) (Raney Ni, NaOH, H20 unstated yields).274... 

The extranuclear hydroxy substrate, ethyl l-(2-hydroxyethyl)-7-(4-methylpiper-azin-l-yl)-4-oxo-l,4-dihydro-l,6-naphthyridine-3-carboxylate, gave its ethyl l-(2-chloroethyl) analog (SOCl2, CHC13, reflux, 2 h 56% analogs likewise).1049... 

The analogous substrate, ethyl 2-(iV-benzyl-iV-ethoxycarbonylmethylamino-methyl)-3-pyridinecarboxylate (15), gave only a nucleus-reduced product, ethyl 7-benzyl-5-hydroxy-7,8-dihydro-l,7-naphthyridine-6-carboxylate (16)... 

Phenyl-2//-pyrido 2,3-<7 [l,3]oxazine-2,4(l//)-dione (64) with diethyl malo-nate gave ethyl 4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-l,8-naphthyridine-3-carboxylate (65) (reactants, NaH, 150°C 85%) 453,407 the same substrate (64) with ethyl nitroacetate gave 4-hydroxy-3-nitro-l-phenyl-1,8-naphthyr-idin-2(lfl)-one (66) (NaH/MeCONMe2, 100°C 77%).1191... 

Ethyl l-ethyl-7-phenyl-6-methoxy- (5, R = Me) gave ethyl 1-ethyl-7-phenyl-6-hydroxy-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylate (5, R = H) (AICI3, CH2CI2 81% note that the unactivated methoxy group would be resistant to regular hydrolysis).1061 Also other examples 402,769... 

Ethyl l-ethyl-6-hydroxy- (13, R = H) gave ethyl 6-benzyloxy-l-ethyl-7-methyl-4-oxo-1,4-dihydro-l,8-naphthyridine-3-carboxylate (13, R = CH2Ph) (PhCH2Cl, K2C03, AcNMe2 98%).1060... 

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