8-Nitro-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
[CAS# 33887-02-4]

Identification

• Classification: Organic raw materials >> Heterocyclic compound
• Name: 8-Nitro-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
• Synonyms: 6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
• Molecular Formula: C₁₇H₁₂ClN₅O₂
• Molecular Weight: 353.76
• CAS Registry Number: 33887-02-4
• EC Number: 998-918-8
• SMILES: CC1=NN=C2N1C3=C(C=C(C=C3)[N+](=O)[O-])C(=NC2)C4=CC=CC=C4Cl

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Boiling point: 576.0±60.0 ºC 760 mmHg (Calc.)^*
• Flash point: 302.1±32.9 ºC (Calc.)^*
• Index of refraction: 1.748 (Calc.)^*
• Solubility: Practically insoluble (0.064 g/L) (25 ºC), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08 Danger
• Hazard Statements: H372
• Precautionary Statements: P260-P264-P270-P319-P501

Discovory and Applicatios

8-Nitro-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is a heterocyclic compound belonging to the triazolobenzodiazepine class, characterized by a fused triazole and benzodiazepine ring system. Its molecular formula is C17H12ClN5O2. The structure contains a 1,4-benzodiazepine core fused with a 1,2,4-triazole ring at the 1,2-positions of the diazepine ring. A nitro group at position 8 and a 2-chlorophenyl substituent at position 6 further modify its electronic and steric properties, while a methyl group at the N1 position enhances lipophilicity.

The discovery of this compound is part of the development of triazolobenzodiazepines, which were synthesized to improve upon the pharmacological properties of classical benzodiazepines. Triazole fusion and substitution patterns influence receptor affinity, metabolic stability, and duration of action. The incorporation of electron-withdrawing groups such as nitro and chloro substituents alters the electron density of the ring system, affecting interaction with gamma-aminobutyric acid type A (GABA_A) receptors.

Synthesis of 8-nitro-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine generally involves condensation of appropriately substituted o-phenylenediamine derivatives with triazole-forming reagents to construct the triazole ring, followed by N-methylation and introduction of the nitro and chloro substituents through selective electrophilic aromatic substitution. Reaction conditions are carefully controlled to ensure regioselective formation of the fused ring system and to avoid overreaction. Purification is achieved through recrystallization or chromatographic techniques to isolate the compound in high purity.

Chemically, the compound exhibits properties characteristic of benzodiazepine and triazole derivatives. The fused heterocyclic system provides rigidity and aromaticity, while the nitro group serves as an electron-withdrawing moiety, influencing electronic distribution across the molecule. The triazole ring enhances hydrogen-bonding potential and contributes to receptor interactions. The N1-methyl group modifies lipophilicity and metabolic profile, affecting solubility and pharmacokinetics.

Pharmacologically, triazolobenzodiazepines act primarily as positive allosteric modulators of GABA_A receptors. Binding at the benzodiazepine site increases chloride ion flux in neurons, resulting in hyperpolarization and central nervous system depressant effects. Substituents on the fused ring system, such as the 2-chlorophenyl and nitro groups, influence receptor affinity, potency, and selectivity, as well as metabolic stability. These structural modifications can alter onset and duration of anxiolytic, sedative, hypnotic, and anticonvulsant activities.

From a physical perspective, the compound is typically a crystalline solid with low solubility in water but high solubility in polar organic solvents such as dimethyl sulfoxide and ethanol. It is generally stable under ambient conditions but should be protected from strong acids or bases that could hydrolyze the diazepine or triazole rings. Handling precautions include avoiding inhalation, ingestion, or skin contact, as the compound can be pharmacologically active and potentially toxic in small doses.

Overall, 8-nitro-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is a structurally and pharmacologically significant triazolobenzodiazepine. Its fused heterocyclic system, halogen and nitro substitutions, and N1-methylation confer receptor binding specificity, lipophilicity, and metabolic stability. The compound serves as a key scaffold for research in medicinal chemistry, particularly in the development of central nervous system-active agents with enhanced potency, selectivity, and pharmacokinetic profiles.

References

2023. Non-fatal intoxications involving the novel benzodiazepine clonazolam: case series from the Emerging Drugs Network of Australia � Victoria project. Clinical Toxicology, 61(4).
DOI: 10.1080/15563650.2023.2183105