Advice on Alprazolam synthesis route

[Pryor]

Hello! I'm new to this forum but really like the community feel of this place. I would love to hear if anyone can confirm that the below method for alprazolam synthesis is viable? If so, would also love some advice on how to best scale this up. Thanks!

Step 1: Synthesis of Nordiazepam​

Reagents:​

• 2-Amino-5-chlorobenzophenone — 0.232 g (1 mmol)
  
  
• Chloroacetyl chloride — 1.2 mL (2 mmol)
  
  
• NH₄OAc — 0.23 g (3 mmol)
  
  
• K₂CO₃ — 0.42 g (3 mmol)
  

Procedure:​

1. Place 0.232 g of 2-amino-5-chlorobenzophenone in a 50 mL round-bottom flask.
   
   
2. Begin vigorous stirring (magnetic stir bar).
   
   
3. Add 1.2 mL chloroacetyl chloride dropwise over 30 minutes at room temperature.
   
   
4. After 30 minutes, add 0.23 g NH₄OAc and 0.42 g K₂CO₃ directly to the flask.
   
   
5. Continue stirring for 2.5 hours at room temperature.
   
   
6. Monitor reaction via TLC.
   
   
7. Add 30 mL distilled water, filter the precipitate.
   
   
8. Wash the solid with 2 × 100 mL cold water.
   
   
9. Dry the solid. No purification required.
   

Yield: ~94%,​

Product: Nordiazepam, mp 212–214 °C​

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Step 2: Synthesis of Acetylated Derivative​

Reagents:​

• Nordiazepam — 0.27 g (1 mmol)
  
  
• K₂CO₃ — 0.55 g (4 mmol)
  
  
• KOH — 0.22 g (4 mmol)
  
  
• Acetic anhydride — 0.18 mL (2 mmol)
  

Procedure:​

1. In a 50 mL flask, mix 0.27 g of nordiazepam with K₂CO₃ and KOH powders.
   
   
2. Add 0.18 mL acetic anhydride.
   
   
3. Stir vigorously at room temperature (optionally 30–40 °C).
   
   
4. Reaction time: 3 hours.
   
   
5. After TLC confirms completion, add 3 × 10 mL water.
   
   
6. Filter and wash product.
   
   
7. Dry the solid; no further purification needed.
   

Yield: ~80%​

Product: Acetylated diazepine, mp 163–165 °C​

---

Step 3: Cyclization to Alprazolam​

Reagents:​

• Acetylated intermediate — 0.31 g (1 mmol)
  
  
• Hydrazine hydrate — 0.2 mL (4 mmol)
  
  
• Sodium acetate — 0.2 g (or ~0.2 mL solution)
  
  
• Acetic acid — 25 mL
  

Procedure:​

1. In a 100 mL round-bottom flask, dissolve 0.31 g of the acetyl intermediate in 25 mL glacial AcOH.
   
   
2. Add 0.2 mL hydrazine hydrate and NaOAc.
   
   
3. Attach a reflux condenser and reflux for 12 hours.
   
   
4. Monitor the reaction by TLC.
   
   
5. After cooling to room temperature, filter the precipitate.
   
   
6. Wash with cold water.
   
   
7. Dry, then recrystallize from ethanol.
   

Yield: ~75%​

Product: Alprazolam, mp 228–230 °C​

 

[synonymousmoose]

Of course this is viable. For scaling up it depends how much you want to scale it up. I wonder if acetyl chloride can be used for acylation. Because acetic anhydride is harder to get.

 

[Pryor]

Thanks, Synonymousmoose! I'm not sure about the substitution but have a source for acetyl chloride so should be okay. If I were to scale this up to, say, 100g or 500g end product do you think just doing the same thing as the above but with larger lab equipment is realistic. Sometimes scaling things up messes up the whole process but I'm not sure about this one.