Pyridazinecarboxylic acids

Pyridazine aldehydes and ketones with the carbonyl group at the ring or in a side chain react in the usual manner. They form hydrazones, semicarbazides, oximes, etc. Side-chain aldehydes can be easily oxidized to pyridazinecarboxylic acids with silver nitrate and side-chain ketones are oxidized to carboxylic acids by treatment with potassium permanganate or hydrogen peroxide. 

Pyridazinecarboxylic acids can also be prepared by hydrolysis of esters, nitriles and amides in the presence of acids or alkali. Another interesting method is partial decarboxylation of... 

Pyridazinecarboxylic acids are more acidic than benzoic acids, due to the electronegativity of the pyridazine ring, but oxopyridazinecarboxylic acids are weaker than the corresponding pyridazinecarboxylic acids (Table 11). 

Condensation of 4-pyridazinecarboxylic acid with tert-butylamine and CDI opens the way to the corresponding sterically hindered Af-terr-butylcarboxamide [28]... 

While in CHEC(1984) <1984CHEC(2)1> there is an emphasis on decarboxylation reactions of pyridazinecarboxylic acids and the choice of esterification methods, in CHEC-II(1996) <1996CHEG-II(6)1> more examples of reactions with pyridazinecarboxylic esters appeared. More recently, the aminolysis of 1,2-diazinecarboxylic esters such as... 

Azinecarboxylic acids lose C02 significantly more easily than benzoic acid. Pyridinecarboxylic acids decarboxylate on heating with increasing ease in the order (3 < < y < a. 2-Pyridazinecarboxylic acid gives pyrazine at 200°C, and 4,5-pyrimidinedicarboxylic acid forms the 5-mono-acid on vacuum distillation. Pyrone- and pyridone-carboxylic acids also decarboxylate relatively easily thus, chelidonic acid (680 Z = O) at 160°C over copper powder and chelidamic acid (680 Z=NH) at 260°C give (681 Z = 0, NH). 

Hydroxymethylpyridazines are easily oxidized with selenium dioxide to the corresponding aldehydes. Oxidation of the corresponding secondary alcohols with chromic acid in aqueous sulfuric acid gives ketones, while oxidation of a hydroxymethyl group with permanganate leads to the pyridazinecarboxylic acids. Hydroxymethyl groups are converted into chloromethyl groups with thionyl chloride or phosphorus oxychloride. 

Produced from 450.5 g of 2,3,4,4a,5,6,7,8-octahydro-3-oxo-6-pyrido[4,3c]pyridazinecarboxylic acid ethyl ester and 320 g of bromine. The bromine is added dropwise to a boiling solution of the ester in 200 cc of chloroform over one hour and the mixture is stirred for another hour at the same temperature. 1 kg of ice water is added to the mixture, the chloroform portion is separated, and the acid aqueous phase is again extracted with 500 cc of chloroform. The semicrystalline crude product obtained after concentrating the chloroform phase, is recrystallized with 250 cc of absolute ethanol, melting point 165°C to 168°C (decomp.). 

A simple and efficient route to these furopyridazines involves 5-aroyl-4-pyridazinecarboxylic acid derivatives (199) reaction with thionyl chloride affords the corresponding furopyridazines (200) in high yield (Equation (69)) <85LA167>. 

The isomeric 6-hydroxy-2-pyrone (glutaconic anhydride) and its 4-methyl analog (47) react similarly with aryldiazonium salts and on hydrolysis with dilute alkali or acid the hydrazones (48) are transformed into l-aryl-6-oxo-l,6-dihydro-3-pyridazinecarboxylic acids or their 4-methyl analogs (49) in variable yields (28-74%). 

Decarboxylation of pyridazinecarboxylic acids usually presents no difficulty and it has been carried out by heating the acid alone or in sulfuric acid, generally over 200°. Decarboxylation of 4,5-pyrida-ziriedicarboxylic acid has been discussed earlier (Section II). Removal of both carboxyl groups has been performed with 3,6-diphenyl-4,5-pyridazinedicarboxylic acid and 4-oxo-l,4-dihydro-3,6-pyridazine-dicarboxylic acid, but more frequently stepwise decarboxylation is reported. The 4-carboxyl group is usually split off first from a 4,5-pyridazinedicarboxylic acid or 6-oxo-l,6-dihydro-3,4-pyrida-zinedicarboxylic acid, but not in the case of a 3,4-pyridazine-dicarboxylio acid where the 3-carboxyl is removed. ... 

The trimethylsilyl ester of 3-pyridazinecarboxylic acid reacts with aldehydes and ketones through ipso substitution of the ester group to give 82. The silyl group can be removed in hot ethanol or with pyridinium trifluoroacetate to give 83 (88T3281). 

Chlorophenyl)-5-hydroxypyridazin-3(2//)-one (7a) and 4-amino-1-(4-chlorophenyl)-6-oxo-l,6-dihydro-3-pyridazinecarboxylic acid (9) can be smoothly iodinated in the C-4 and C-5 position, respectively using I2 in aqueous Na2CO3/dioxane at reflux [18]. Chlorination and bromination of methyl l-(4-chlorophenyl)-4-hydroxy-... 

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