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Synthesis of 6,7,8,9‐tetrahydro‐5 H ‐pyrimido‐[4,5‐ b ][1,4]diazepine‐6,8‐diones
Author(s) -
Phillips Oludotun A.,
Knaus Edward E.
Publication year - 1993
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570300148
Subject(s) - chemistry , diazepine , sodium hydride , oxcarbazepine , sodium ethoxide , medicinal chemistry , stereochemistry , organic chemistry , ring (chemistry) , epilepsy , neuroscience , ethanol , biology , carbamazepine
The sodium ethoxide catalyzed condensation of 4,5‐diaminopyrimidine ( 3 ) with diethyl malonate afforded 6,7,8,9‐tetrahydro‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 4 ). Methylation of 6,7,8,9‐tetrahydro‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 4 ) using sodium hydride and two equivalents of iodomethane gave 5,9‐dimethyl‐6,7,8,9‐tetrahydro‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 5 ) which on further methylation using sodium hydride and one equivalent iodomethane yielded 6,7,8,9‐tetrahydro‐5,7,9‐trimethyl‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 6 ). Reaction of 6,7,8,9‐tetrahydro‐5 H ‐pyrirnido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 4 ) with 4.2 equivalents of sodium hydride and 4.1 equivalents of iodomethane afforded 6,7,8,9‐tetrahydro‐5,7,7, 9‐tetramethyl‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 7 ). 6,7,8,9‐Tetrahydro‐5,7,7,9‐tetramethyl‐5 H ‐pyrimido[4,5‐ b ][1,4]diazepine‐6,8‐dione ( 7 ) exhibited weak anticonvulsant activities in the subcutaneous pentylenetetrazole and maximal electroshock anticonvulsant screens indicating it is a partial bioisostere of the anticonvulsant drug clobazam ( 2 ).