Synthesis of 5-phenyl-10-methyl-7H- pyrimido[4,5-f][1,2,4]triazolo[4,3-a][1,4]diazepine and its evaluation as an anticonvulsant agent

Abstract

The homolytic benzoylation (benzoyl radical) of 5-tert-butylcarbonylaminopyrimidine (6, 1 equiv.) in the presence of benzaldehyde (3 equiv.), water, sulfuric acid, and acetic acid, upon treatment with FeSO4·7H2O (3 equiv.) and 70% t-BuOOH (3 equiv.) at 5-10°C for 10 min afforded a mixture of 4-benzoyl-5-tert-butylcarbonylaminopyrimidine (7, 23%), 4,6-dibenzoyl-5-tert-butylcarbonylaminopyrimidine (8, 44%), and 4-benzoyl-5-tert-butylcarbonylamino-6- methyl pyrimidine (9, 10%). When a similar reaction was performed using 1 equiv. each of PhCHO, FeSO4·7H2O, and t-BuOOH, to prevent formation of the 4,6-dibenzoyl product 8, the monobenzoyl (7, 38%) and 4-benzoyl-6-methyl (9, 6%) products were obtained. A similar homolytic benzoylation of 5-bromopyrimidine (10) using 1.5 equiv. of reagents to generate the benzoyl radical afforded 4-benzoyl-5-bromopyrimidine (11, 61%) as the predominant product. Elaboration of 11 via a six-step reaction sequence afforded 2-hydrazino-5-phenyl-3H-pyrimido[5,4-e][1,4]diazepine (17) in 5.2% overall yield. The acid-catalyzed reaction of 17 with triethyl orthoacetate gave the title compound 5-phenyl-10-methyl-7H-pyrimido[4,5-f][1,2,4]triazolo[4,3-a][1,4]diazepine (18, 62%). The triazolo compound 18 was more potent than valproic acid (Depakene(r)) in both the subcutaneous metrazol (scMet) and maximal electroshock (MES) anticonvulsant screens, and more potent than clonazepam in the MES anticonvulsant screen but less potent than clonazepam in the scMet anticonvulsant screen.Key words: homolytic benzoylation, pyrimidines, pyrimidodiazepines, anticonvulsants.