3-pyridazinone 6-methyl

A simple fragmentation pattern is also characteristic for chloro-, methyl- and amino-pyridazines. Pyridazinone fragments by loss of carbon monoxide followed by loss of N2 (Scheme 2). 

IV-Methylated pyridazinones can be obtained from 3,6-dialkoxypyridazines by treatment with alkyl halides or dialkyl sulfates. Methyl iodide and dimethyl sulfate are most frequently used. According to the proposed mechanism, an intermediate quaternary pyridazinium salt is formed, followed by elimination of a group R from the alkoxy group. At higher temperature, l,2-dimethylpyridazine-3,6(l//,2//)-dione is formed with dimethyl sulfate. 

The Michael-type addition of maleic hydrazide and other pyridazinones to activated alkenes, such as methyl acrylate, acrylonitrile, methyl vinyl ketone and other a,/3-unsatu-rated carbonyl compounds, results in the formation of mono-lV-substituted products. 

Since pyridazinones are acidic compounds, they undergo IV-hydroxy- and N-amino-methylation. They react also with aromatic aldehydes in the presence of acetic anhydride in the ratio of 2 1 to give the condensation product (73 Scheme 23). 

IV-Methylation of polysubstituted pyridazinones is frequently accompanied by some side reactions, mainly substitutions. For example, methylation of 4-nitro-5,6-diphenyl-pyridazin-3(2//)-one with methyl iodide in the presence of sodium methoxide affords... 

The dipolar cycloaddition of 2-diazopropane to l-methyl-3-phenylpyridazin-6(l//)-one takes place through an unstable adduct which thermally decomposes to a 1,2-diazepinone, a pyridazinone and diazanorcaradiene derivative (Scheme 46). 

Acrylic acid, -(3-benzo[f>]thienyl)-a -mercapto-reaction with iodine, 4, 764 Acrylic acid, o -cyano-y3-(2-thienyl)-ring opening, 4, 807 Acrylic acid, -formyl-in pyridazinone synthesis, 3, 46 Acrylic acid, furyl-rotamers, 4, 545 synthesis, 4, 658 Acrylic acid, 2-hydroxybenzoyl-chroman-4-one synthesis from, 3, 850 Acrylic acid, 5-(l-propynyl)-2-thienyl-methyl ester occurrence, 4, 909 Acrylonitrile... 

Keywords biocatalytic [4 + 2] cycloaddition reactions of cyclopentadiene, 2-vinylpyridine and 2-methyl-3-pyridazinones with various dienophiles, yeast... 

CN 4,5-dihydro-6-[2-(4-methoxyphenyl)-l/7-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone hydrochloride... 

Another pyridazinone-derived inotropic agent with cAMP phosphodiesterase inhibitory activity is pimobendan [UD-CG-115-BS CAS 74150-27-9, (21)], which has been developed in Germany. In contrast to the imidazolyl-phenylpyridazinone CI-930 (16) discussed above, in pimobendan the imidazole nucleus (substituted at C-2 by a 4-methoxyphenyl group) is fused to the benzene moiety attached to C-6 of the 4,5-dihydro-5-methyl-3(2//)-pyri-dazinone system. 

The annelation of benzo rings on pyridazines was covered in CHEC-II(1996) <1996CHEC-II(6)1>. Maes and Matyus reported new examples in their synthesis of the dibenzo[// ]phthalazin-l(27r)-one and dibenzo[//]cinnolin-3(27/)-one skeleton. Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one yielded 2-benzyldibenzo[/,4]phthalazin-l(2//)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl) -phenylpyridazin-3(2//)-one via a Pschorr-type reaction was also investigated. Similarly, the con-stmction of 2-methyldibenzo[/, ]cinnolin-3(2//)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(27T)-one and 2-methyl-5-(2-aminophenyl)-6-phenyl-pyridazin-3(2//)-one was performed <2003T5919>. 

The synthesis of pyrrolo[2,3- 7 pyridazines can be achieved by starting either with pyridazine, a tetrazine, or a pyrrole. Pyridazinone 80 reacts with bromomethyl derivatives to give poor yields of 81 <1996H(43)1863> (Equation 34), while 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone, after treatment with sarcosine ethyl ester for a brief time at room temperature, followed by acid hydrolysis afforded a good yield of 82 (70%) <1994S669>. 

Nuclear Overhauser effect (NOE) difference measurements were used to assign structure 79 for the product of reaction of diphenylnitrile imine with 5-ethylsulfonyl-2-methyl(27/)pyridazinone. Thus in the H NMR spectrum the ot/, o-protons of the arylhydrazino moiety (which were identified by two-dimensional heteronuclear multiple quantum correlation (2-D HMQC) spectroscopy) were shown in differential NOE (DNOE) experiment to be significantly enhanced on irradiation of pyridazine hydrogen H-7, proving their steric proximity <2000JST13>. 

The reaction of the 5-substituted-2-methyl-3(2-77)pyridazinone 383 with nitrile imine 384 generated in situ from the corresponding hydrazonoyl halide has been shown to afford 387 rather than 388. The formation of 387 is believed to proceed via the intermediacy of 385 (Scheme 33) <2000JST13>. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

On the other hand, reaction of 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone 287 with A -methyl-/3-alaninenitrile afforded the 4-(2-cyanoethyl) derivative 288, which was cyclized by heating with sodium ethoxide in ethanol to the pyrido[2,3-rflpyridazine 289 (Equation 22) <1994S669>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Pyridazines (see Sections II, IV, V,C,1, and V,D-G). Product ratios for the quaternization of 3- and 4-methylpyridazines and their NMR spectra have been reported.155 Betaine (49) is prepared by heating 3(2//)-pyridazinone (50) with methyl tosylate to 130° in kerosene followed by deprotonation of the resultant cation with an exchange resin. Interestingly, both Mel and methyl sulfate react under alkaline conditions with the pyridazinone at the other annular nitrogen atom.156... 

Unsubstituted pyrazino[2,3-d]pyridazine (14) is prepared by the reaction of 4,5-diaminopyridazine (216) with glyoxal. Reaction of this starting pyridazine with pyruval-dehyde produces the methyl substituted product (217) (66JHC512). Similarily, pyrazino-[2,3-d]pyridazin-5-one (218) can be prepared by the reaction of 4,5-diamino-3-pyridazinone with glyoxal (69JHC93). 

This procedure is similar to the previous one, except that the cyclization happens on the carbon at the /3-position of the nitrogen atom. The synthesis of oxazepine 145 started with the reaction of 4,4 -dichloro-2-methyl-3-(2//)-pyridazinone 142 with 3-benzylamino-l-phenylpropen-l-ol 143. The obtained product 144 was cyclized in basic conditions to the desired 1,4-oxazepine 145 (Scheme 20) <1996JHC583>. 

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