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Jul 5, 2021
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The work presented here has shown the opportunity of Clonazolam synthesis (also known as Clonitrazolam; 6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine). This synthesis path let scale up reaction and increase the reaction yield. There do not need to use difficult laboratory techniques or expensive glassware. However, you have to find quite unusual reagents and be careful with them.

Equipment and glassware:

  • Pear shaped round bottom flasks 20 ml X2;
  • TLC kit (optional);
  • Heated magnetic stirrer;
  • Retort stand and clamp for securing apparatus;
  • Laboratory scale (0.01 — 100 g is suitable);
  • Pasteur pipette's;
  • Water-jet aspirator (optional);
  • Buchner flask and funnel (or small Schott filter);
  • Conventional funnel;
  • Filter paper;
  • Reflux condenser (small);
  • Beakers 100 ml x2; 50 ml x4; 10 ml x2;
  • Glass rod;
  • Measuring cylinder for 10 ml and 100 ml;
  • Separatory funnels 50 ml X2;
  • Rotary evaporator (optional);
  • Water/oil bath.

  • 2‐Amino‐2′‐chloro‐5‐nitrobenzophenone 1.66 g, 6 mmol;
  • 2‐Chloro‐1,1,1‐triethoxyethane 1.38 g, 6.9 mmol;
  • Glacial acetic acid 378 mkL;
  • Toluene 5 mL;
  • Sodium bicarbonate (Na2CO3) ~50 g;
  • Anhydrous magnesium sulfate (MgSO4) ~50 g;
  • Acetone 60 mL;
  • Sodium iodide (NaI) 1.35 g, 9 mmol;
  • Dichloromethane (CH2Cl2) ~50 mL;
  • Distilled water, ~1 L;
  • Sodium thiosulfate (Na2S2O3) 2 g;
  • Ethanol (EtOH) 60 mL;
  • Sodium azide (NaN3) 780 mg, 12 mmol;
  • Ethyl acetate (EtOAc) ~50 mL;
  • Tetrahydrofuran 30 mL;
  • Triphenylphosphine 1.89 g, 2.4 mmol;
  • Hexane ~100 mL;
  • Acetylhydrazine (acethydrazide), 90%, 29 mg, 0.35 mmol;
  • Methanol, 3 mL + ~50 mL;
  • Tert‐butyl methyl ether ~50 mL.
Boiling Point: 524.5 ± 50.0 at 760 mm Hg;
Melting Point: 229 °C – 231 °C;
Molecular Weight: 353.77 g/mol;
Density: 1.5±0.1 g/ml (20 °C);
CAS Number: 33887-02-4.


A mixture of 2‐amino‐2′‐chloro‐5‐nitrobenzophenone (1.66 g, 6 mmol), 2‐chloro‐1,1,1‐triethoxyethane (1.38 g, 6.9 mmol), glacial acetic acid (360 μL), and toluene (5 mL) was refluxed for 6 hours in the 20 ml pear shaped round bottom flask. After cooling to room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried (anhydrous magnesium sulfate) and the volatiles were removed to afford a brown oil, which was dissolved in acetone (60 mL).
Sodium iodide (1.35 g, 9 mmol) was added, and the mixture was stirred at room temperature for 5 hours and then evaporated to dryness. The residue was partitioned between dichloromethane and water (containing a small amount of sodium thiosulfate). The organic layer was collected and dried (anhydrous magnesium sulfate). Removal of the solvent afforded a brown oil (2.62 g).
This was dissolved in ethanol (60 mL) and sodium azide (780 mg, 12 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated to a small volume under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was collected and evaporated to afford a brown oil (2.36 g), which was dissolved in tetrahydrofuran (30 mL).
Water (600 μL) and triphenylphosphine (1.89 g, 2.4 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness to afford a brown oil (3.76 g). A portion of this (960 mg) was purified by preparative thin layer chromatography (TLC) (silica gel, 2 mm; hexane/ethyl acetate, 7/3) to afford a light‐yellow powder (158 mg): m.p. 119°C–121°C;
6‐(2‐Chlorophenyl)‐1‐methyl‐8‐nitro‐4H‐[1,2,4]triazolo[4,3‐a][1,4]benzodiazepine (clonazolam)
A solution of 5‐(2‐chlorophenyl)‐2‐ethoxy‐7‐nitro‐3H‐benzo[e][1,4]diazepine (100 mg, 0.29 mmol), acetylhydrazine (acethydrazide, 90 %, 29 mg, 0.35 mmol) and glacial acetic acid (18 μL) in methanol (3 mL) was stirred for 48 hours at room temperature.
The volatiles were moved under vacuum and the residue was triturated with methyl tert‐butyl ether to afford a yellow powder (99 mg). This was heated (sand bath at 225 °C) for 10 minutes under reduced pressure to afford yellow powder. This was purified by preparative TLC (silica gel, 2 mm; ethyl acetate/methanol, 9/1) and triturated with tert‐butyl methyl ether to afford an almost colorless solid (50 mg, 0.14 mmol, 48 %) m. p. 231 °C –233 °C (lit. 229 °C –231 °C).
Last edited:


New member
Feb 7, 2022
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Great contribution man, clonazolam is by far one of my favorite benzos. Would also be interested in some literature for other legal benzos like flualprazolam or etizolam.


Active member
Dec 27, 2021
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I would also be interested in the synthesis of Etizolam, does anyone have experience with it? It was the only benzo I liked, but currently all the sourcees have dried up.
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