G.Patton
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Introduction
I would love to represent you this simple method of Xanax (Alprazolam; Xanor, Niravam; 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) synthesis. It doesn't take elaborated glassware or exotic reagents, all used techniques are extremely simple. Nevertheless, chemist have to pay attention to safety and use PPE.
Equipment and glassware:
- Pear-shaped flask 10-50 ml and 100 ml;
- Reflux condenser;
- Conventional funnel;
- Filter paper;
- TLC kit (optional);
- Drip funnel (20 ml);
- Heated magnetic stirrer;
- Retort stand and clamp for securing apparatus;
- Laboratory scale (0.01 — 100 g is suitable);
- Pasteur pipette's;
- Vacuum desiccator (optional);
- Water-jet aspirator (optional);
- Beakers 100 ml x2; 50 ml x2; 10 ml x2;
- Glass rod;
Reagents:
- 2-Amino-5-chloro benzophenone 0.232 g, 1 mmol;
- Chloroacetyl chloride 1.2 mL, 2 mmol;
- Ammonium acetate (NH4OAc) 0.23 g, 3 mmol;
- Potassium carbonate (K2CO3) 0.97 g, 7 mmol;
- Distilled water, 1 L;
- Potassium hydroxide (KOH) 0.22 g, 4 mmol;
- Acetic anhydride 0.18 mL, 2 mmol;
- Hydrazine hydrate (N2H5OH) 4 mmol, 0.2 mL
- Acetic acid AcOH 25 ml;
- Ethanole (EtOH) 100 ml 95%.
Boiling Point: 509.0±60.0 °C at 760 mm Hg;
Melting Point: 228-228.5 °C;
Molecular Weight: 308.765 g/mol;
Density: 1.4±0.1 g/ml (20 °C);
CAS Number: 28981-97-7.
Procedures
Synthesis of 7-chloro-5-phenyl-1H benzo[e][1,4]diazepin-2(3H)-one (nordiazepam) (1)To a vigorously stirred of 2-amino-5-chloro benzophenone (0.232 g, 1 mmol) in a pear-shaped flask (10-50 ml), chloroacetyl chloride (1.2 mL, 2 mmol) was added drop wise at room temperature under solvent-free conditions during 30 min and the progress of reaction was monitored by TLC. After completion of the reaction, NH4OAc (0.23 g, 3 mmol) and K2CO3 (0.42 g, 3 mmol) were added to the mixture at room temperature under solvent-free conditions and stirred for 2.5 h. When the reaction was completed, as it was shown by TLC, the water (30 mL) was added and the product was filtered off via paper filter, washed with more distilled water (2 x 100 mL) and dried in vacuum desiccator. The product was obtained in high yield and purity (94% yield) and was used in the next step without any purification. m.p. = 212–214 °C.
Synthesis of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]-diazepin-2(3H)-one (2)
To a vigorously stirred mixture of nordiazepam (1) (0.27 g, 1 mmol) in a pear-shaped flask (10-50 ml), a powder mixture of K2CO3 (0.55 g, 4 mmol)/KOH (0.22 g, 4 mmol) and acetic anhydride (0.18 mL, 2 mmol) was added. The progress of the reaction was monitored by TLC. After completion of the reaction (3 h), water (3 x 10 mL) was added and the 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2) was easily isolated by a simple filtration in more than 80% yield with high purity. The product was used in the next step without any purification. m.p. = 163–165 °C.
To a vigorously stirred mixture of nordiazepam (1) (0.27 g, 1 mmol) in a pear-shaped flask (10-50 ml), a powder mixture of K2CO3 (0.55 g, 4 mmol)/KOH (0.22 g, 4 mmol) and acetic anhydride (0.18 mL, 2 mmol) was added. The progress of the reaction was monitored by TLC. After completion of the reaction (3 h), water (3 x 10 mL) was added and the 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2) was easily isolated by a simple filtration in more than 80% yield with high purity. The product was used in the next step without any purification. m.p. = 163–165 °C.
Synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (Alprazolam, Xanax) (3)
A solution of 1 mmol (0.31 g) of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2), hydrazine hydrate N2H5OH (4 mmol, 0.2 mL) and NaOAc (4 mmol, 0.2 mL) in 25 ml of AcOH was refluxed for 12 h in a pear-shaped flask (100 ml) with a reflux condenser. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was cooled and the product was filtered, washed with water, dried, and crystallized from EtOH. (75% yield); m.p. = 228–230 °C.
A solution of 1 mmol (0.31 g) of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2), hydrazine hydrate N2H5OH (4 mmol, 0.2 mL) and NaOAc (4 mmol, 0.2 mL) in 25 ml of AcOH was refluxed for 12 h in a pear-shaped flask (100 ml) with a reflux condenser. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was cooled and the product was filtered, washed with water, dried, and crystallized from EtOH. (75% yield); m.p. = 228–230 °C.
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