Pyrido pyridazine-3-carboxylate

Acetyl (79GEP2808070,71FES1074) and Other groups on the pyridine ring have been oxidized to the corresponding carboxylic acids in the pyrido-[2,3-c]- and -[3,4-d]-pyridazine fields. Acid groups in pyridopyridazines behave normally on esterification (66CPB1010). 

The only example from a pyridazine intermediate is of the Dieckmann-type used so widely in the pyridopyrimidine field (Section 2.15.5.4.2). The 3-carboxyalkylamino-4-ester (365) is cyclized by strong base to give the pyrido[2,3-c]pyridazine-6-carboxylate (366) (77JAP(K)7733695). 

The thermal cyclization of 3-pyridazinylaminomethylenemalonate N-oxide (1052) by heating in diphenyl ether at 250°C for 15 min gave pyrido[2,3-c]pyridazine-6-carboxylate jV-oxide (1053) in 70% yield (72JHC351). 

Dehydrogenation of ethyl 2-methyl-4-hydroxy-5,6,7,8-tetrahydro-4a//-pyrido]l,2-/j]pyridazine-3-carboxylate with mercury(II) acetate in ethanol at 45-50°C or over PtOa in boiling ethanol afforded anhydro 3-ethoxycar-bonyl-2-methyl-4-hydroxy-5,6,7,8-tetrahydropyrido[l,2-h]pyridazinium hydroxide (48) (71CPB159). The last compound could be reduced to the starting tetrahydropyrido[l,2-h]pyridazine over Pt02 in ethanol under hydrogen. 

Dieckmann condensation of piperidine-2-carboxylate 138 in toluene in the presence of NaOEt furnished pyrido[l,2-h]pyridazine-3-carboxylate (139) (71CPB159). Ethyl 2-methyl-4-hydroxy-5,6-dihydro-4a//-pyridaz-ino[l,6-a]quinoline-3-carboxylate (7,8-benzolog of 139) was prepared similarly (66YZ613). 

Condensation of 3-ethoxycarbonyl-, 3-acetyl-, or 3-cyano-l,2,3,4-tetrahydropyridine -carboxylic acid derivatives 275-277 with hydrazine hydrate in boiling ethanol afforded the pyrido[3,4-r/ pyridazine derivatives 278-280, respectively (Equation 20) <2002PS1359>. 

Ring transformation of ethyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- pyrimidine-5-carboxylates 317 with 80% hydrazine hydrate in boiling ethanol gave a mixture of 5-methyl/allyl/benzylamino-l,2,3,4-tetrahydro-l,4-dioxopyr-ido[3,4-i/ pyridazines 318, pyrido[2,3,4-< <7]pyridazino[3,4-/ [l,2,4]triazepines 319, and a low yield of 2,3,4,6,7-penta-azaphenalene 320. The reaction of 317 with hydrazine hydrate was also performed without a solvent in an oil bath at 125 °C for 1 h to give the same products, but higher yields of 318 and lower yield of 319 as well as traces of 320 were obtained (Equation 25) <1997FA657>. 

Reaction of l-aminopiperidine-2-carboxylates 27 and (benzo[l,2,4]thiadia-zin-3-yl)acetic acid 28 in the presence of DCC, followed by the treatment with NaOEt afforded pyrido[l,2-fc]pyridazin-2-ones 3 (08BML5002, 08WOP2008 /073987). 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

Ethyl 4-ChIoro-6-fluoro-7-(4-tolylsulfanyI)pyrido 2,3-c pyridazine-3-carboxylate (2) Typical Procedure 12... 

Ethyl 4-chloro-6-fluoro-7-(4-tolylsulfanyl)pyrido[2,3-< ,]pyridazine-3-carboxylate (2 1.13 g, 3.0 mmol) in anhyd THF (5 mL) was added below 0 °C to a stirred solution of NaOF.t (224 mg, 3.3 mmol) in anhyd F.tOH (15 mL). After an additional 15-min period of stirring, the mixture was kept below 10°C for 1.5 h, then neutralized with 1 M HOAc, and concentrated to dryness in vacuo. After addition of CHC13 and ice-water, the organic layer was separated and dried. The solvent was evaporated in vacuo, and the residue was chromatographed (silica gel, CHCI3/ F.tOAc), followed by recrystallization (EtOAc) yield 380 mg (30%) colorless prisms mp 165 °C. 

Mixing aqueous solutions of sodium 3-formyipyridine-2-carboxylate and hydrazine hydrochloride gives pyrido[2,3-af]pyridazin-8(7//)-one (8).37... 

Benzoylpyridine-2-carboxylic acid is condensed with hydrazine or phenylhydrazine to give the corresponding pyrido[2,3-rf]pyridazin-8(77/)-ones 10.48 30... 

In a similar fashion, as carboxylic acids or their esters, certain carboxamides possessing an ortho acyl group tnay also cyclocondense with hydrazine. Thus, Ar,/V-dicthyl-3-(2-pyridy car-bonyl)pyridine-2-carboxamide gives the corresponding pyrido[2,3-(i]pyridazin-H(7//)-one 15 in 89% yield, whereas, in contrast, 3-benzoyl-A, Ar-diisopropylpyridine-2-carboxamide and hydrazine give jV,2V-diisopropyl-5-phenylpyrido[2,3-d]pyridazin-8-amine (16) in 42% yield.50... 

In a related reaction sequence, either arylhydrazones of diethyl 3-amino-2-cyano-4-oxopent-enedioate or their cyclization products, the corresponding ethyl 4-amino-l-aryl-5-cyano-6-oxo-l,6-dihydropyridazine-3-carboxylates react with malononitrile or ethyl cyanoacetate to give pyrido[2,3-d]pyridazine-2,5(1 f/,6//)-diones 2 or 3.71... 

In hot alkaline solution pyrido[2,3-c/]pyridazine is oxidized by potassium permanganate to give 4-aminopyridazine-5-carboxylic acid together with a small amount of pyridine-2,3-dicarboxylic acid.83... 

The following modifications of substituents without alteration of the pyrido[3,4-r]pyridazine system have been performed oxidation alkenes to carboxylic acids (ArCH=CHPh - ArC02H) 104 condensation methyl groups with carbaldehydes (ArMe- ArCH = CHPh) Ar = pyridolT -elpyridazinyl.104... 

Hydrazinolysis of dimethyl pyridine-3,4-dicarboxylate gives the hydrazinium salt of a pyridine-3,4-dicarboxylic acid monohydrazide, thought to be the 4-carboxylic acid 1. The hydrazinium salt or free acid, respectively, on heating at 365-370°C cyclizes to give pyrido[3,4-t/]-pyridazine-1,4-(2//,3//)-dione (2).117... 

Although not a typical reaction of the pyrido[4,3-c]pyridazine ring system, the acylation at N6 of 4,8-dialkyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazinc with numerous carboxylic acid chlorides is worthy of mention.142... 

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