The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido5,4-c]pyridazin-8-one ( 38 ). Pyrimido5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.