Identification and synthesis of O-methylcatechol metabolites of phenobarbital and some N-alkyl derivatives.

5-Ethyl-5-(4-hydroxy-3-methoxyphenyl) barbituric acid was identified as a new, minor metabolite of phenobarbital in man. The identity of this O-methylcatechol metabolite was confirmed by an unequivocal chemical synthesis, and by GC-MS studies. Mephobarbital and the 1,3-dimethyl, 1-ethyl, and 1,3-diethyl analogues of phenobarbital yielded the corresponding N-alkylated O-methylcatechol metabolites, all of which were confirmed by synthesis. The N-alkyl barbiturates each gave additionally at least one O-methylcatechol metabolite in which N-dealkylation had occurred. These metabolites accounted for approximately 1-5% of the orally administered dose in man.