SYNTHESIS OF 6-AMINO-1-BENZYL-4-METHYLHEXAHYDRO-1H-1,4-DIAZEPINE

Five variants (methods A-E) of a synthetic route to 6-amino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine (3b) using N-benzyl-N'-methylethylenediamine (8a) are described. The reaction of 8a with 1-benzenesulfonyl-2-bromomethylaziridine (7), 2-phenyl-4-(p-toluenesulfonyloxymethyl)oxazoline (13), and beta,beta-dibromoisobutyric acid (15) resulted in the direct cyclization to give the precursor of 3b, 6-substituted 1,4-diazepine derivatives 9, 14, and 16, respectively (methods A-C). These compounds were transformed into the desired 3b. The preparation of 1,4-diazepine ring from methyl 2-tert-butoxycarbonylaminopropenate (18) was alternatively achieved by the intramolecular amidation of the intermediate 19a (method D) or reductive cyclization of the aminoaldehyde 23a (method E). Method E was found to efficiently produce the 6-amino-1,4-diazepine 3b.