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

• Published in: Bioorganic & medicinal chemistry Vol. 3; no. 4; pp. 391 - 395
• Main Authors: Maehr, H, Zenchoff, G, Coffen, D L
• Format: Journal Article
• Language: English
• Published: England 01-04-1995
• Subjects: AIDS/HIV; Benzodiazepines - chemical synthesis; Benzodiazepines - pharmacology; Gene Products, tat - antagonists & inhibitors; HIV-1 - drug effects; Humans; Magnetic Resonance Spectroscopy; Methylamines - chemistry; Models, Molecular; Molecular Structure; Pyrroles; tat Gene Products, Human Immunodeficiency Virus; Virus Replication - drug effects
• ISSN: 0968-0896
• DOI: 10.1016/0968-0896(95)00026-D

An alternative synthesis of 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-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-(1H-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)-5H-pyrrolo[1',2':3,4]- 1,3,6,2-oxadiazabora[6,5-d]-8H-1,4-benzodiazepin-7-ium hydroxide inner salt. This unusual benzodiazepine does not significantly inhibit Tat-mediated gene expression by HIV-1.