3-Pyridazinone synthesis

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... 

Pyrimido[5,4-c]pyridazin-8(2i/)-one, 6- N,N-dimethylamino)-2-phenyl-synthesis, 3, 357 Pyrimido[l, 2-6]pyridazin-2-ones H NMR, 3, 333 IR spectra, 3, 335 synthesis, 3, 354, 355 Pyrimido[ 1,2-6]pyridazin-4-ones synthesis, 3, 354, 355 Pyrimido[4,5-c]pyridazinones chlorination, 3, 344 Pyrimido[4,5-d]pyridazin-5-ones... 

Pyrrolo[3,4-d]pyridazinium salts, 2,3-dimethyl-synthesis, 4, 291 Pyrrolo[ 1,2-6]pyridazinones oxidation, 4, 298 Pyrrolo[2,3-6]pyridine, 1-acetyl-cycloaddition reactions, 4, 509 Pyrrolo[2,3-6]pyridine, 3-bromo-nitration, 4, 505... 

Bicyclic lactams 189 are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-277-pyridazinones 190 by hydrolysis with NH2NH2 and HC1 in dioxane at 85 °C. The reaction gave, as a side product, the ketoacid 191 in some cases (Equation 32) <2003TL7997>. 

Quite recently, a French group reported on the synthesis of 2-substituted 5-arylidene-pyridazinones as represented by the general formula (21, R1 = Ph, 2-ClC6H4 R2 = Ph(CH2)2, PhCO). These compounds were found to exhibit significant dose-dependent analgesic activity (phenylquinone-induced writhing test in mice oral administration) [92]. For a novel type of aminopyridazine-derived inhibitors of prostacyclin biosynthesis, see [93],... 

Barbaro, R., Betti, L., Botta, M., Corelli, F., Giannaccini, G., Maccari, L., Manetti, F., Strappaghetti, G. and Corsano, S. (2001) Synthesis biological evaluation, and pharmacophore generation of new pyridazinone derivatives with affinity toward alpha(l)- and alpha(2)-adrenoceptors. Journal of Medicinal Chemistry, 44, 2118-2132. 

In the United States, compound RGW-2938 (47) has been developed as a selective positive inotropic agent its synthesis and pharmacological actions have been reviewed [161]. Related compounds, in which the dihydro-pyridazinone system is replaced by a benzoxazinyl system instead of the quinazoline system, have recently been studied in India and in the United States [162,163]. From this series, bemoradan (48) was found to be a very potent orally active, long-acting inotropic vasodilator agent in canine models (i.v. ED5o = 5.4 //g/kg 24h duration of action) [163]. 

It is not surprising to see that most of the bio-active compounds discussed in this review are 1,2-diazine derivatives bearing heteroatom substituents either at C-3 or at C-3 and C-6, since pyridazinones and pyridazinediones, utilized as intermediates in the synthesis of such derivatives, have been known for a long period and are generally conveniently accessible. On the other hand, there are so far only a few examples of pyridazine-derived pharmacological agents in which the parent system is linked to a functionalized carbon side-chain only. This may be attributed to the fact that many of the required synthetic building blocks had remained unexplored until very recently [15,173,438-441]). 

Nitro derivatives of several halogenated pyridazin-3(2//)-ones have been prepared by treating the pyridazinones with a mixture of a nitrate salt and acetic anhydride or trifluoroacetic anhydride <2003JOC9113>. These compounds have been used for the synthesis of nitramines (see Section 8.01.8.3). 

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>. 

The role of the pyridone ring as a pharmacophore in cardiotonic agents such as amrinone (25-6) has been noted earlier very analogous activity is obtained with compounds in which the heterocylic ring is replaced by a pyridazinone. The synthesis of the first of these agents, pimobendan (35-6), starts with the acylation of the amino group in nitro-aniline (35-2) with anisoyl chloride (35-1) to give amide (35-3). 

Only one unrefuted synthesis of this ring system has been reported in the literature (76MIP21700). A mixture of (142) and the desired ring system (143) are reported as the products from the reaction of the anhydride (141) with an excess of hydrazine hydrate in water at reflux temperature for 3.5 hours. If the reaction is carried out using equimolar amounts of the starting anhydride and hydrazine hydrate in aqueous ethanol for 5 days, the formation of the pyridazinone (144) is reported. 

The same principle was applied to the synthesis of the pyridazinone derivatives 417 with a fluorine nucleus (63ZOB1974). One can use peri-... 

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>. 

F., Barlocco, D., Dal Piaz, V., Leonardi, A., Poggesi, E., Fanelli, F., De Benedetti, P. G. Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disub-stituted-3-(2H)-pyridazinone analogues as new substrates for ai-adrenoceptor selective antagonists synthesis, modeling and binding studies. Bioorg. Med. Chem. 1998, 6, 925-935. 

A practical method for the synthesis of chiral pyridazinone bearing a pyrazolopyridine ring via lipase-catalyzed resolution of 2-(acyloxymethyl)-4,5-dihydro-5-methylpyridazin-3(2H)-one derivatives 113 was reported by Yoshida et al.95... 

Yoshida, N. Aono, M. Tsubuki, T. Awano, K. Kobayashi, T. Enantioselective synthesis of a chiral pyridazinone derivative by lipase-catalyzed hydrolysis. Tetrahedron Asymmetry 2003, 14, 529-535. 

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