2.3.4.5- Tetrahydro-3-pyridazinones

Relatively few pyridazine derivatives occur in natur, e.g. the quaternary salt pyridazinomycin 20. Some pyridazine derivatives show biological activity and are applied as herbicides and anthelmintics, e.g. maleic hydrazide 18 and the chlorinated pyridazinones 21 (pyrazon)/22 (pyridaben). The tetrahydro-pyridazinone derivative levosimendan 23 is an innovative myofilament calcium sensitizer applied as cardiotonic in treatment of heart failure. 

A solution of 223.2 g of 6concentrated hydrochloric acid is heated to the boil at reflux for 22 hours while stirring. The mixture Is concentrated in a vacuum, and the resulting crude crystalline hydrochloride of 5,6,73-tetrahydro-3(2H)pyrido[4,3melting point of 307°C to 310°C (decomposed from methanol), is suspended in 0.75 liter of methanol, and... 

Tetrahydro-6-Oxopyridazinecarbonyl Azide. C5H5Ns02 mw 167.15 N 41.91% OB toC02 —100.5 l% mp 135° (with expln). Prepn is by treating the ethyl ester of 3-carboxy-4,5-dihydro-6(lH)-pyridazinone hydrazide hydrochloride with Na azide (Curtius reaction)... 

A solution of 223.2 g of 6-carbethoxy-5,6,7,8-tetrahydro-3(2H)pyrido[4,3-c]pyridazinone in 1 liter of concentrated hydrochloric acid is heated to the boil at reflux for 22 hours while stirring. The mixture is concentrated in a vacuum, and the resulting crude crystalline hydrochloride of 5,6,7,8-tetrahydro-3(2H)pyrido[4,3-c]pyridazinone, having a melting point of 307°C to 310°C (decomposed from methanol), is suspended in 0.75 liter of methanol, and 0.4 liter of triethylamine is slowly added to the suspension. After stirring for 15 minutes and cooling the violet suspension, the crude base is obtained. 25 g of the crude base are recrystallized from 300 cc of methanol, mixed with 10 cc of concentrated ammonia and 40 cc of water, with the addition of a small amount of coal. 5,6,7,8-Tetrahydro-3(2H)pyrido[4,3-c]pyridazinone has a melting point of 223°C to 225°C (decomp.). 

The palladium- or platinum-catalyzed hydrogenation of various pyrido[2,3-of]pyridazinones gives the 1,2,3,4-tetrahydro compounds. Thus, the respective 1,2,3,4-tetrahydro derivatives are... 

Many new pyridazine, cinnoline, and phthalazine syntheses relied on the use of hydrazine-based precursors. 4,5-Dihydro-3(2//)-pyridazinones were obtained by cyclization of hydrazine with Meldrum s acids <97SC3513>, and six-membered cyclic hydrazides 3 were obtained in very high diastereoselectivities by the coupling of azide-substituted bisfenol silanes) <97JOC5680>. PhSeBr-promoted cyclization of alkenyl phenylhydrazones led to tetrahydro-pyridazines <97T7311>, condensation of furofuranones and hydrazines led to pyrrolo[2,3-... 

Methyl-5-phenylsulfonyl-3(2iJ)-pyridazinone (152, R = SOaPh) underwent Diels-Alder addition by 2,3-dimethyl-l,3-butadiene (151) to give 2,6,7-trimethyl-4a-phenylsulfonyl-4a,5,8,8a-tetrahydro-1 (2fl)-phthalazinone (153, R = S02Ph) (reactants, PhH, reflux, 10 days 90%) methyl l-methyl-6-oxo-l,6-dihydro-4-pyridazinecarboxylate (152, R = C02Me) likewise gave methyl 2,6,7-trimethyl-1 -oxo-1,2,4a,5,8,8a-hexahydro-4a-phthalazinecarbox-ylate (153, R = C02Me) (70%) such additions by an unsymmetric diene... 

Bromobutyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-l(2//)-phthala-zine with 6-p>-hydroxyphenyl-5-methyl-5,6-dihydro-3(2//)-pyridazinone gave 4-(3,4-dunethoxyphenyl)-2- 4-[p-(4-methyl-6-oxo-l,4,5,6-tetrahydropyridaz-in-3-yl)phenoxy]butyl -4a,5,8,8a-tetrahydro-l(2H)-phthalazinone (106) (reactants, K2CO3, trace KI, Me2NCHO, 60°C, >3 h 35%) analogs likewise. o... 

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