4- Chloro-3-nitro-l,6-naphthyridine

Tlie effect of substituents on chemical shifts in H NMR spectrum of 4-chloro-3-nitro-l,6-naphthyridine (78b), when compared with those of the parent 1,6-naphthyridine, show that all corresponding proton signals in 78b are shifted downfield in the range of 0.09 to 0.72 ppm. Tlie downfield of H-2 is particularly large 0.72 ppm (75MI1). 

Bromo- (35, R = Br) with dimethylamine gave 4-dimethylamino-l,6-naphthyr-idine (35, R = NMe2) (neat reactants, 135°C, sealed, 16 h %)1057 but 4-chloro- (35, R = C1) gave 4-piperidino-l,6-naphthyridine [35, R = N(CH2)5] apparently under milder conditions (neat reactants, 95°C, 5 min %)1067 4-chloro-3-nitro-l,6-naphthyridine (36, R = C1) gave 3-nitro-l,6-naphthyridina-mine (36, R = NH2) (NH3/MeOH, 110°C, sealed, 4h 75%).819... 

Deuterio-3-nitro-l,6-naphthyridine (168) was prepared from 4-chloro-3-nitro-l,6-naphthyridine (166) by a reaction with tosyl hydrazide and subsequent hydrolysis of the 4-tosylhydrazino derivative (167) with Na2C03/ D20 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). This deuterio compound could be converted into 2-chloro-(or 2-ethoxy-) 7-deuterio-3,6-dinitro-l,8-naphthyridine. 

Nitro-1,6-naphthyridin-2( 1 //)-one gave 2-chloro-3-nitro-1,6-naphthyridine (10) (POCl3, reflux, 3 h 44%) 819 4-chloro-8-nitro-l,6-naphthyridine (75 min 68%)48 and 5-chloro-8-iodo-l,6-naphthyridine (likewise 64%)1042 were made similarly from the corresponding 1,6-naphthyridinones. 

Analogously, 4-chloro-8-nitro-l,6-naphthyridine (80, 68%) (63JCS4237), 8-chloro-5-nitro-l,7-naphthyridine (97,51%) (78JHC731),and 2-chloro-3,6-dinitro-l,8-naphthyridine (82, 66%) (85JHC761) were obtained from 8-nitro-1,6-naphthyridine-4(lH)-one, 5-nitro-l, 7-naphthyridin-8(7H)-one, and 3,6-dinitro-l,8-naphthyridin-2(lH)-one, respectively. 

Chloro-1,6-naphthyridin-4( l/7)-one 2-Chloro-3-nitro-1,6-naphthyridin-4-amine... 

Chloro-3-nitro-1,8-naphthyridine 7-Chloro-3-nitro-l,8-naphthyridin-2(l//)-one 7-Chloro-6-nitro-l,8-naphthyridin-2(l//)-one... 

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). 

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). 

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). 

The slurry was filtered, and the compound was isolated as a white solid (75.5% yield based on (la,5a,6a)-3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane 96.6% based on ethyl 7-chloro-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid). The ethyl (la,5a,6a)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3yl)-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate was recrystallized from acetonitrile, melting point 148°-155°C decomp. 

Ethyl l-(2-chloroethyl)-6-nitro-4,7-dioxo-l,4,7,8-tertahydro- gave ethyl 7-chloro-1 -(2-chloroethyl)-6-nitro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-boxylate (13) [POCl3, Me2NCHO (i.e., a Vilsmeier reagent), 65°C 82%].1029... 

Ethyl 7-chloro-6-nitro-4-oxo-l, 4-dihydro-l,8-naphthyridine-3-carboxylate 195-197 364... 

In a very similar way the corresponding 7-amino-substituted compounds (103a-103p) were obtained from ethyl 7-chloro-l-ethyl-l,4-dihydro-6-nitro-4-oxo-l,8-naphthyridin-4(lH)-one 3-carboxylate (102) (77MI2 79YZ155 80CPB235). 

Thiazolo[5,4-b]naphthyridines [CsNS-CsN-C N]. The reaction of 6-amino-1 -ethyl-7-mercapto-1,4-dihydro-4-oxonaphthyridine-3 -carboxylic acid with acid anhydrides or acid chlorides and ethyl xanthate yields the title compounds (177). It is also possible to obtain this ring system in one step, starting from ethyl 7-chloro-l-ethyl-6-nitro-l,4-dihydro-4-oxonaphthyridine-3-carboxylate and potassium thiocyanate in acetic acid. ... 

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