Chapter 19. 1,4-Benzodiazepine derivatives

Chlosepide, nitrazepam, phenazepam

Structure: a bicyclic system.

aromatic benzene ring

1,4-benzodiazepine (3H-1,4-benzodiazepine)

5-phenyl-1,4-benzodiazepine

1,2-dihydro-3H-1,4-benzodiazepin-2-one

Chlosepide (Chlordiazepoxide, Elenium) Chlozepidum 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4 oxide

Derivatives of 1,2-dihydro-5-phenyl-3H-1,4-benzodiazepin-2-one.

Nitrazepam Nitrazepamum (Eunoctin) 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2-one The yellow compound is due to the nitro group

Phenazepam Phenazepamum (Russian-made drug) 7-bromo-5-(o-chlorophenyl)-3H-1,2-dihydro-1,4-benzodiazepin-2-one

General chemical structure

In most substances there is an amide bond ⇒ acidic properties. An azomethine bond is present in position 4-5. A phenyl radical. A covalently bonded halogen or a nitro group in position 7.

Description

All substances are white crystalline powders; Nitrazepam is yellow. Insoluble in water. Melting point, IR spectrum, UV spectrum.

Identification

1. Acid-base properties.
2. Oxidation reactions.
3. Formation of colored melts.
4. Hydrolysis and determination of hydrolysis products.
5. Covalently-bonded halogen.
6. Other reactions.

1. Acid-base properties:

All substances are mainly ampholytes with predominantly basic properties. They are most pronounced in Chlosepide. Predominance of acidic properties is also possible.

1. Amide bond, acidic properties ⇒ solubility in NaOH solutions; salt-forming and complexation reactions with heavy metal salts. Co²⁺ salts have the characteristic shape of crystals.
2. Basic properties are due to the azomethine bond ⇒ solubility in mineral acids, complexation reactions with general alkaloid precipitation reagents: Dragendorff’s, Mayer’s.

2. Oxidation reactions

Phenazepam: drug + HClO₄ ⇒ when heated ⇒ yellow-green coloration with intense fluorescence in UV light.

3. Formation of colored melts

Occurs during severe oxidation. Phenazepam is a violet or red-violet melt, with its color depending on pH: NaOH gives it a blue-violet tint and diluted H₂SO₄ (16%) results in a yellow-green one.

4. Hydrolysis and determination of hydrolysis products

Acid hydrolysis (!):

1. Products of hydrolysis are colored yellow.
2. Possible formation of an azo dye:

For assay, the nitritometric method is used (the final product is a diazonium salt)

Nitrazepam-specific features: the formation of azo dye in two positions (if heated with zinc dust + HCl).

5. Covalently-bonded halogen

1) Beilstein’s preliminary test. Copper wire + drug ⇒ light green coloration of the flame.

а) Conversion to an ion by oxidation (combustion in a flask with oxygen; fusion with Na₂СО₃ + КNO₃; concentrated H₂SO₄) or reduction (zinc + NaOH; zinc + H⁺).

b) Validation of the ion at optimal рН:

1) + diluted HNO₃ + AgNO₃ ⇒ AgCl ↓ AgBr ↓;

+ (NH₄)₂CО₃ ⇒ Ag(NH₃)₂Cl - clear solution or yellow AgBr ↓;

2) Сl^-; Br^- + Ar-SO₂-NClNa (chloramine) + HCl + СНCl₃ ⇒ orange coloration of the chloroform layer (Br₂).

Assay

1) All substances are quantitatively determined by acid-base titration in a non-aqueous medium as one-acid bases according to the general principle:

2) Nitritometry.

3) Kjeldahl method.

4) HPLC ― with a reference standard.