Pyridazin-6-ones carboxylic acids

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Other 1,2-diazines synthesized included 4-amino-3-cinnolinecarboxylic acids <97PHA91 >, I -aryl-6-chloro-l,4-dihydro-4-oxothieno[2,3-c]pyridazine-3-carboxylic acids <97JPR284>, 2H-benzo[2,3-g]pyridazino[4,5-<7,e]quinolin-3-ones <97M681>, 3-chloro-4-carbamoyl-5-aryl-6-methylpyridazine N-oxides <97F67>, 2-aroyl-6-(hetero substituted)-3(2//)-pyridazinones <97HCM267>, and 5-(4-hydroxycinnolin-3-yl)tetrazoles 2-methyl-5-(4-acetoxycinnolin-3-yl)-... 

Moran et al. recently reported receptor 20 that contains two pyridazine-2,4-dione units as polar anchor groups anellated to an aromatic framework [28] as well as the xanthone compound 21 where one of the binding sites is a ben-zoylamido group [29]. Compound 20 fits the binding pattern required for malonic acids, whereas 21 forms complexes with aromatic carboxylic acids like p-ethoxybenzoic add in CDCI3. 

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... 

The methyl group in ethyl 5-methylpyridazine-4-carboxylate can be converted by reaction with dimethylformamide dimethyl acetal to the 2-(dimethylamino)vinyl group (see Houben-Weyl, Vol. E9a, p 649), which may serve as a C-C unit for the annulation of a pyridine ring. Thus, ethyl 5-[2-(dimethylamino)-l-phenylvinyl]pyridazine-4-carboxylate reacts with ammonia or benzylamine in acetic acid/ethanol at elevated temperatures to give 8-phenylpyrido[3,4-r/]-pyridazin-5(6//)-one (4a) or the 6-benzyl derivative 4b.67 Similar condensations have been carried out with ethyl 5-[2-(dimethylamino)vinyl]pyridazine-4-carboxylate and ammonia or butylamine.131... 

The synthesis of 2-benzenesulfonylpyridazin-3(2//)-ones has been discussed in Section 8.01.5.5.4. They can be used to prepare A -alkylbenzenesulfonamides via reaction with aliphatic amines <2002JHC203>. 4,5-Dichloro-2-[(4-nitrophenyl)sulfonyl]pyridazin-3(27/)-one proved to be useful for the preparation of carboxylic anhydrides from the corresponding acids in the presence of base in THF or CH2CI2 <2003S1517>. 

Pyrazino[2,3-d]pyridazine-5,8-dione (420) can be prepared from pyrazine-2,3-dicarboxylic acid anhydride (419). Condensation of hydrazine with ethyl 5-acylpyridazine-4-carboxylates (421) gives pyridazino[4,5-d]pyridazin-l(2//)-ones (422) (79M365). 

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). 

Ethyl 3-[2-(dimethylamino)vinyl]pyridazine-4-carboxylatc, obtained by condensation of ethyl 3-methylpyridazine-4-carboxylate with icrt-buLoxy-/V-ditneLhylmethanediamine (Bredereck s reagent, see Houben-Weyl, Vol. E5, p 151 f), cyclizes with alkylamines in acetic acid to give the corresponding 6-alkylpyrido[3,4-c/]pyridazin-5(6//)-ones 5.7... 

In contrast to the reaction of many 3-aminopyridazines with DMAD and acetylenemono-carboxylates, to give pyrimido[l,2-Z>]pyridazin-2(2//)-ones (see e.g., <83H(20)2225 , 6-amino-3(2//)-pyridazinone reacts by a Michael-type addition to give the aminobutenedioate (Scheme 58), which can be cyclized in acetic acid to the isomeric pyrimido[2,l-f)]pyridazin-4(47/)-one system. Condensation of 3-aminopyridazines and 6-amino-3(2//)-pyridazinones with diethyl ethoxymethyl-enemalonate proceeds in the expected Michael fashion to give aminomethylenemalonates which can be cyclized thermally <88JHC1535>. 

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