Pyrido cinnolin

This representation is intended to encompass 4-oxo-3-quinolinecarboxyhc acids as well as the corresponding 1,8-naphthyridines, cinnolines, and pyrido[2,3-<55pyrimidines. These classes are illustrated by ciprofloxacin [85721-33-1] (2) (1), naUdixic acid [389-08-2] (3) (2), cinoxacin [28657-80-9] (4) (3), and piromidic acid [19562-30-2] (5) (4), respectively. 

Surprisingly, no fully detailed syntheses of pyridopyridazines by joining of two heteroatoms have been recorded, although a recent patent claimed the preparation of pyrido-[2,3-c]-, -[3,2-c]-, -[3,4-c]- and -[4,3-c]cinnolines by reduction of 2,2 -dinitro substituted phenylpyridines with a variety of reagents (80GEP2939259). 

An important early method simulated the well-known Widman-Stoermer cinnoline synthesis. 3-Aminopyridine-2- or -4-alkenes such as (348) gave pyrido-[3,2-c]- or -[3,4-c]-pyridazines on diazotization and alkaline cyclization (66JCS(C)2053>. 

Reactions involving quinoline hydrazide derivatives have been noted in the pyridazino-[4,3-c]- (64MI21500), -[4,5-f ]- (31M(58)238) and -[4,5-c]-quinoline (71CB3341) series, whilst the double cyclization of (358) to the pyridazino[4,5-f ]quinoline (359) (80CPB3457) and related cyclizations in the same series (80H(14)267) are of a basically similar type. A lone cyclization of this type from cinnoline intermediates involves the o-acetonylcarboxamide type formation of the pyridine ring to give the pyrido[3,4-c]cinnoline (360) (76JCS(Pl)592). 

The only example of a simple pyridopyridazine synthesis of this kind from a pyridine intermediate involves a variant of a well known cinnoline synthesis in which the Japp-Klingemann intermediate (363) gives the pyrido[3,4-c]pyridazine (364) with PPA (69JHC977). 

Pyrido[2,3-c]cinnolines synthesis, 3, 242, 245 Pyrido[3,2-c]cinnolines synthesis, 3, 242, 245 Pyrido[3,4-c]cinnolines synthesis, 3, 242, 244, 245 Pyrido[4,3-c]cinnolines synthesis, 3, 242, 245 Py rido[ 18]crown-6 t-butylammonium complex... 

X-ray investigations on 3,3-bis(tcrt-butoxycarbonyl)-4,5-difluoro-l-methyl-7-oxo-2,3-dihydro-l//,7//-pyrido[3,2,l-(/]cinnoline-8-carboxylate 57 revealed, that 1-methyl group is perpendicular to the plane of the 4-quinolone moiety (96BCJ1371). 

The cyclization of diethyl A[-(4-methylcinnolin-8-yl)aminomethylene-malonate in diphenyl ether at 245°C for 20 min gave pyrido[3,2-/i]cinnoline-8-carboxylate (610) in 31% yield (51JOC1414). 

The values of perhydropyrido[l,2-f)]pyridazine and its 2-oxo derivative were found to be 2.80 0.04 and 7.32 0.03, respectively (72KGS220), whereas that of anhydro 4-hydroxy-2-methyl-5,6,7,8-tetrahydropyrido(l,2-6]pyridazinium hydroxide (16) was determined by spectrophotometry to be 2.77 (71CPB159). UV spectroscopic measurements in sulfuric acid gave a pKa value of -0.25 for pyrido[l,2-6]cinnoline derivative (17, R = H) (74JHC125). 

The Structure of a pyrido[l,2-6]cinnoline (17, R = Br) (74JHC125), a pyrido[2,l-a]phthalazine (26) (94T9189), and 2,4-diphenyl-7-o-hydroxyphe-nyl-5,6-dihydropyrido[2,l-fl]phthalazinium perchlorate (27) (95IZV296) have been established by X-ray crystallographic analysis. 

Ring-opened products were obtained from pyrido[l,2-6]cinnolin-6-ium hydroxide inner salt (17, R = H) by oxidation with 3-chloroperoxybenzoic acid, or by reduction with Zn in acetic acid, and from the 5-methyl derivative 43 by reduction with Zn in acetic acid (74JHC125). 

Nitration of pyrido[l,2-f>]cinnolin-6-ium hydroxide inner salt 17 (R = H) and its 2-acetamide derivative afforded its 2-nitro and 2-acetamido-3-nitro derivatives, respectively. The reaction of 17 (R = H) with iodine monochloride afforded the 2-iodo derivative. The 2-cyano derivative was obtained from the 2-bromo derivative of 17 (R = H) with Cu(I)CN. Treatment of 17 (R = H) with P4S10 afforded the 11-mercapto derivative 41 (74JHC125). 

Methyl 5-fluoro-4-(trifluoromethylsulfonyloxy)-2,3-dihydro-l-methyl-7-0X0-1//,7//-pyrido[3,2,l-iy]cinnoline-8-carboxylate(68,R = Me,R = R = H, R = F, R = Me, R = CF3SO2O) was reacted with 3-tributylstannyl-2-cyclohexen-l-one in the presence of lithium chloride and bis(triphenyl-phosphine)palladium(II) chloride in tetrahydrofuran for 3 days to give a 4-(3-oxo-l-cyclohexen-l-yl)derivative (92EUP470578). 

The 1-hydroxymethyl group of l-hydroxymethyl-7-oxo-l//,7//-pyrido [3,2,l-y]cinnoline-8-carboxylate (81) was O-alkylated by treatment with diethylaminosulfur trichloride and an alcohol in THE. The 4-hydroxy group of 4-hydroxy-7-oxo-l//,7//-pyrido[3,2,l-t7]cinnoline-8-carboxylate... 

Heating ethyl 5-fluoro-4-[cyano(ethoxycarbonyl)methyl]-2,3-dihydro-l-methyl-7-oxo-l//,7//-pyrido[3,2,l-i7]cinnoline-8-carboxylate (83, R = COOEt) in a mixture of cone. HCl and acetic acid gave the 8-carboxy-4-acetic acid derivative (92EUP470578). The acetic acid group was decarboxylated by heating in boiling ethanol in the presence of NEts to give the 4-methyl derivative. When the 4-[cyano(tert-butoxycarbonyl)methyl]-8-carboxylate 83 (R = COOrBu) was treated with trifluoroacetic acid in methylene chloride at room temperature, the 4-cyanomethyl-8-carboxylate 83 (R = H) was obtained. 

Nonaqueous hydrolysis of pyrido[3,2,l-iy]cinnoline-3,3,8-triearboxylate (86) in TEA gave 8-ester-3-carboxylic acid derivative (87, R = Et)... 

The crystal structure of ethyl 4-(4-rert-butoxycarbonyl-l-piperazinyl)-5-fluoro-2,3-dihydro-l-methyl-2,7-dioxo-l//,7//-pyrido[3,2,l-iy]cinnoline-8-carboxylate (186, R = Et, R = tert-Qu, R = 4-tm-butoxycarbonyl-l-piperazinyl) was determined by means of X-ray diffraction investigation [95T11125]. 

No further reports were found for pyrimido[4,5-g]quinazolines, pyridazino[4,5-g]cinnolines, pyridazino[4,5-g]phtha-lazines, pyrido[2,3-g]quinoxalines, cyclobuta[l,2- 3,4-i3 ]dipyridines, cycloocta[2,T3 3,4- ]dipyridines. 

Photoirradiation of the mesoionic 1,2,3,4,5,7,8,9,10,11-decahydro-ll-oxopyrido[ 1,2-b]cinnolin-6-ium hydroxide inner salt (433) affected clean intramolecular isomerization to the pyrido[2,1 -b]quinazolin-11 -one (436, 78% yield) through the diaziridine and ketene intermediates 434 and 435... 

Irradiation of the 3-pyridyltetrazolium salt (367) similarly gives a mixture of 5,6-tetrazolo fused derivatives of these systems (368), which can be converted to the parent systems by various reducing agents (75TL569,56CB563). Use of the 4-pyridyl isomer gave the pyrido[4,3-c]cinnoline anologues. 

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