An alternate synthesis of the Tat-antagonist 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine

An alternative synthesis of 7-chloro- N -methyl-5-(1 H -pyrrol-2-yl)-3 H -1,4-benzodiazepin-2-amine, the compound that inhibits gene expression by HIV-1 at the level of transcriptional transactivation by Tat, has been developed. The process is based on ring expansion of 6-chloro-2-chloromethyl-4-(1 H -pyrrol-2-yl)quinazoline 3-oxide which leads to the corresponding benzodiazepine Ro24-7429. Quinazoline 3-oxide formation in the presence of boron trifluoride gives a tetracyclic system containing a 2,2-difluoro-1,3,6,2-oxadiazaborine ring that survives ring expansion to 13-chloro-5,5-difluoro-9-(methylamino)-5 H -pyrrolo[1′,2′:3,4]-1,3,6,2-oxadiazabora[6,5- d ]-8 H -1,4-benzodiazepin-7-ium hydroxide inner salt. This unusual benzodiazepine does not significantly inhibit Tat-mediated gene expression by HIV-1.