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‐methylpyrimido[4,5‐c]pyridazine‐5,7‐dione (2), 3‐methylpyrimido[5,4‐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 pyrimido[4,5‐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‐methylpyrimido[4,5‐c]pyridazin‐5‐one (21). 4‐Aminopyridazine‐3‐carboxamide (36) upon fusion with urea gave pyrimido[5,4‐c]pyridazine‐6,8‐dione (37) while with ethyl orthoformate 36 gave pyrimido[5,4‐c]pyridazin‐8‐one (38). Pyrimido[5,4‐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‐aminopyrimido[5,4‐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 pyrimido[5,4‐c]pyridazine ring system was accomplished by the Reissert reaction of 4‐aminopyridazine‐2‐oxides and subsequent conversion of the nitrile to the amide.