Pyrimido pyridazine-2,5-diones

Pyrimido[4,5-c]pyridazine-5,7-dione, 3-aryl-6,8-dimethyl-synthesis, 3, 357... 

Pyrimido[4,5-d]pyridazine-5,8-dione, 2-aryl-chlorination, 3, 345 Pyrimido[ 1,2-6]pyridazine-2,4-diones synthesis, 3, 355... 

Pyrimido[5,4-c]pyridazine-6,8-diones synthesis, 3, 357 Pyrimidopyridazines rearrangement, 5, 342 Pyrimido[ 1,2- 6]py ridazines HNMR, 3, 334 reactivity, 3, 343... 

JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH2 easily produced 3-(2-oxo-2//-chromen-3-yl)-6//,8//-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenyl-phosphonium salts <05HAC56>. 

The synthesis of 4-trifhioromethylpyrimido[4,5-c]pyridazin-5,7-diones from 6-hydrazinouracils and l,l,l-trifluoropropane-2,3-dione monohydrates has been reported <06H1875>. Novel pyrimido[4,5-c]pyridazines have been synthesized and investigated as inhibitors of lymphocyte specific kinase <06BMCL4257 06H2037>. 

Reaction of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazin-5,7-diones 80 with cyclohexyl and cycloheptylamines afforded novel cycloalkano bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines 81 <06T652>. 

Pyrimido[4,5-d]pyridazine-2,5-diones were synthesized in a similar manner, employing several hydrazines (R3 = H, Me, Ph) for the nucleophilic substitution prior to cyclative cleavage. Due to the high nucleophilicity of the hydrazines, reaction times for the substitution step could be reduced to 30 min. In the case of phe-nylhydrazine, concomitant cyclization could not be avoided, which led to very low overall yields of the isolated products. 

Much of the recently reported work on nucleophilic substitution at C-3 and C-4 of pyrimido[4,5-f]pyridazine-5,7-diones is included in a review of nucleophilic substitution in pyridazines <2001CHE1461>. 6,8-... 

A mechanism has been proposed to account for the formation of each of these products (72YZ1312). Pyrimido[4,5-d]pyridazine-2,4-dione (85) is cleaved by 10% aqueous sodium hydroxide to give 5-hydroxypyridazine-4-carboxylic acid (100). Cleavage with concentrated ammonium hydroxide also occurs, yielding 5-aminopyridazine-4-carboxylic acid (101) (68JHC845). 

The mesomeric betaine pyrimido[l,2-6]pyridazine-2,4-diones (173) have been prepared from 2-aminopyridazines (172) by reaction with bis(2,4,6-trichlorophenyl) methylmalonate. These heterocycles are extremely stable molecules. They have high melting points and are stable to nucleophilic attack by benzylamine in refluxing chloroform, ethanol or acetonitrile for 7 days <76JPS(65)1505). 

Hydrazino-l,3-dimethyluracil (185) reacts with phenacyl bromides in DMF to give the corresponding 3-aryl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7-diones (186). 6-Benzyl-idenehydrazino-l,3-dimethyluracils are also known to react with DMF dimethyl acetal to give pyrimido[4,5-c]pyridazines (78JHC781). 

Pyridazine-3,4-dicarboxamide (187) undergoes the Hofmann reaction followed by ring closure to give pyrimido[4,5-c]pyridazine-5,7-dione (188) as the major product. In an analogous type of ring closure, 3-amino-6-methylpyridazine-4-carboxamide reacts with ethyl orthoformate to give 3-methylpyrimido[4,5-c]pyridazin-5-one (68JHC523). 

Aminopyridazine-3-carboxamide condenses with urea and ethyl orthoformate to give pyrimido[5,4-c]pyridazine-6,8-dione and pyrimido[5,4-c]pyridazin-8-one, respectively. In like manner, 8-aminopyrimido[5,4-c]pyridazine is formed by the reaction of 4-amino-3-cyanopyridazine with formamide (68JHC523). 

Most pyrimido[4,5-d]pyridazines are prepared from 4,5-disubstituted pyridazine precursors. The versatile intermediate pyrimido[4,5-cf]pyridazine-2,4-dione (85) can readily be formed in high yield from pyridazine-4,5-dicarboxamide (196) by reaction with sodium hypobromite in a Hofmann type reaction (68JHC53). 

Diethyl pyrimidin6-4,5-dicarboxylates react readily with hydrazine to give pyrimido-[4,5-df]pyridazine-5,8-diones (72CPB1513). In a similar manner the acyl pyrimidines (202) react with hydrazines to give the products (203) (76BSF1549). Hydrazines also react with... 

Another facile synthesis of pyrimido[4,5-c]pyridazin-5,7(6/7,8//)-diones (51), pyrimido[4,5-c]py-ridazin-5(8//)-ones (52), and dihydropyrimido[4,5-c]pyridazin-5(6//)-ones (53) starts from 3-chloro-4-pyridazinecarbonitrile (48) via aminocarbonitriles (49) and aminocarboxamides (50) (Scheme 9). Cyclization of the latter with urea at high temperatures affords the pyrimido[4,5-c]pyrid-azin-5,7(6/7,8//)-diones (51). By heating of the carboxamides with aromatic aldehydes the dihydropyrimido[4,5-c]pyridazin-5(6/7)-ones (52) are obtained <88JHC119). 

---