Alprazolam (Xanax) synthesis. Small scale.

[KokosDreams]

I'd be interested in hearing about a report too

 

[Agilent1100DAD]

Just waiting on the chloroacetyl chloride to arrive and I’ll have everything I need. I’ll write up a little report about it, I’m looking to scale this up by x100, so I’ll also be playing around with that after the small scale synth. I have access to a copious amount of 2-Amino-5-chloro benzophenone and am willing to share , as well as perhaps make a video on this synthesis.

I believe this is a very important one for people to learn, perhaps since alprozolam is so cheap to make, this would lead to less fentanyl laced Xanax bars. Only one can hope. It’s important to note that the main precursor, 2-Amino-5-chloro benzophenone, is NOT a scheduled precursor!!
@madmoney69
@Hedgie

 

[Field7]

There's "scheduled" and then there's "watched". Long, long list of watched chemicals. Even acetone and 40% Hydrogen Peroxide are watched (depending on part the volume of the purchase). Just about anything anhydrous is watched. "Why does so and so need 4 liters of anhydrous hydrazine shipped to their *apartment?" They're not baking cookies; that's for sure...

 

[Agilent1100DAD]

Alright, I did the first part of the alprazolam synthesis, which involved a “solvent free” procedure. I dropped chloroacetyl chloride into the benzophenone compound over the course of 30 minutes. I then added potassium carbonate and ammonium acetate and let it stir for 2.5 hours. I filtered and washed with water. I got about 75% yield of nordiazepam. Confirmed with MP and TLC.

I will now convert the nordiazepam (after a taste test ) into 1-acetyl-7-chloro-1H-benzo 1,4 diazepin. Then convert that into alprazolam, using hydrazine mono hydrate. I will be doing this step outside lol.

I’m going to redo this step but I’m going to scale up x10. I’ll post photos.

 

[KokosDreams]

Hey there We've been in touch here in the comment section some months ago.
Your profile is closed for DMs, can you reach out to me? I have some things to discuss!

 

[Agilent1100DAD]

@G.Patton

New Update:

Part I out of III, batch 003 (conversion to nordiazepam)

Procedure Used:

"To a vigorously stirred of 2-amino-5-chloro benzophenone (6.93 g, 1 mmol), chloroacetyl chloride (35.8 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 (6.85 g, 3 mmol) and K2CO3 (12.5 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 (300 mL) was added and the product was filtered off, washed with more water (2x 500 mL) and dried. The product was obtained in high yield and purity (94 % yield)"

Interesting enough, the more I scale up, the more yellowish the nordiazepam is.

Anyways, I used the rest of my chloroacetyl chloride (500mL is getting overnighted) up in order to produce the nor diazepam. Something strange happened...usually the solution is a pale yellow, but this time the solution was a red-orange color. The solution solidified! Perhaps all the chloroacetyl chloride was used up? Nonetheless, I proceeded with the wash. I ended up with a yellowish crystalline powder, which still has the right melting point. Im waiting on the Dragendorffs reagent spray to arrive, it will make the TLC analysis much easier. I ended up with 20 g of nordiazepam from the afromentioned batch (003) and a total of 15.3 g from Batch 01-003

Part II out of III, batch 002 (acetylation of nor diazepam)

Procedure Used for batch 002:

"To a vigorously stirred mixture of nordiazepam (1) (2.7 g, 1 mmol), a powder mixture of K2CO3 (5.5 g, 4 mmol)/KOH (2.2 g, 4 mmol) and acetic anhydride (excess 40 mL, 2 mmol) was added. The progress of the reaction was monitored by TLC. After completion of the reaction (3 h), water (3x100 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, with 3x20omL water washes in more than 80 % yield with high purity. The product was used in the next step without any purification."


Batch 001 for Part II was 1/10 of the scale for batch 002, its a simple procedure. My lab tech forgot to put the filter paper on the fritted funnel and some product went through. We re ran the water back into the filter. I am not too happy with batch 001, I see foreign material in the compound and the yield was very low (40%).

Batch 002: I am letting this run overnight.

Conclusion: Once I collect 20 g of the acetylated nordiazepam, I will begin to convert this into alprozolam. Full report with video instructions coming soon

*The two photos added are the comparison between Part I, batch 002 and 003. Batch 002 was yellow and stayed in solution, while batch 003 was a dark orange color and solidified.

 

[Agilent1100DAD]

Forgot to add the photo for Part I Batch 003, just to compare colors.

 

[catmando]

Well done on this, truly excellent work.

I can't get past the first step of this synthesis, I keep ending up with an off white powder MP 118 to 121 which I take is 2-(chloroacetamido)-5-chlorobenzophenone.

Have you got any pointers for me of where I could be going wrong please?

Your help would be greatly appreciated.

 

[Hank Schrader]

I would do the first acylation step in cyclohexane.
By mixing 2-amino-5-chloro benzophenone in cyclohexane and slowly dropping chloroacetyl chloride.


You have written in the method
chloroacetyl chloride (1.2 mL, 2 mmol)
1.2ml of chloroacetichloride is 1.7016g which is not 2mmol.
The molar mass of chloroacetichloride is 112.94.
The ideal ratio for acylation per 1 mol of chloramine is not more than 1.26 mol of chloride in the presence of a solvent.
The presence of a solvent makes it possible to control the temperature and obtain a good yield due to temperature stability and the absence of gumming.

I would carry out the cyclization step in dry methanol with urotropine.

 

[catmando]

How many ml of methanol per gram of benzophenone would would you add say 5ml per gram?
And how much hexamine?

I've attempted the first part of this synthesis a good few times with the same results, an off white powder with m.p. ranging from 118 to 121.

I had given up on this synthesis but after revisiting this thread and seeing the excellent advance agilent1100DAD made I'm going to give it another shot.

I found the "gumming up" of the solvent less mix very difficult to work with, hopefully some alcohol will help.

So just to clarify after the addition of chloride to benzophenone add methanol, potassium carbonate, ammonium acetate and hexamine?

 

[Marc-BenzoScam]

Well I for one have a question if manufacturing Alprazolam is so easy and cost effective why is there such a shortage of it?

 

[G.Patton]

I can't say that synthesis is too easy.

 

[Agilent1100DAD]

I’m a manufacture of all types of benzos

 

[catmando]

How dry was ammonium acetate and what was the purity of it?

 

[ging6910]

Can you pm me please

 

[catmando]

I've attempted the first part of this synthesis a few times with no success, I keep getting an off white powder mp 118 g 121.

In part 1 of this synthesis will traces of water in regents affect success? How important is it to have all regents completely anhydrous?

The ammonium acetate I have is 97% would this be the problem?
I have been drying it in a desiccator with silica gel beads at 35c to 40c.
Is this ammonium acetate ok or do you think I need ammonium acetate that's 99%+ ?

I've had trouble with the "solventless" mix gumming up, it's difficult to stir (I don't have an over head stirring) could this also be a problem?

 

[catmando]

Sorry, I know I'm answering my own question but regents not been completely anhydrous shouldn't have any effect on this synthesis, as any traces of water in contact with chloroacetyl chloride would rapidly hydrolyse into HCL gas making them anhydrous.

Once an excess of chloroactyle chloride is used a little water shouldn't matter should it?

 

[LazZzZz]

Could acetyl chloride be a suitable replacement when it comes to the acetylation of the 2ndary amine to the acetyl tertiary amine?
Also, wouldnt the first step need to use 2-aminoacetic acid chloride for the formation of the imine?

 

[mithyl2]

how high up can this synthesis realistically be scaled up?

 

[experimentsci]

Hallo, I already tried the first step of the solvent-free-synthesis.
WITHOUT success, It is very hard to mix the first two reagents without any solvents.
It became a very sticky mass, wich was not able to stirr anymore.
After some some some time I was goind on with this first step. My result was looking good, but the laboratory I send it to, told me that the
result is just 2-Amino-5-chloro benzophenone.

So I made a lot of work just for changeing the optic apperance of 2-Amino-5-chloro benzophenone....

Maybe someone had better experience with it than I had.

Or Maybe someone have another route for the synthesis of Alprazolam.

Best regards

 

[riderofapocalypse]

Sorry guys, this synth will not produce first compound. https://www.researchgate.net/public...he_result_of_a_failed_synthesis_of_alprazolam

If u want just diazepam - erowid, last synth is fine!
https://patents.google.com/patent/CN104130201B/en - working synth for alprazolam

 

[experimentsci]

Thank you a lot for this information. Do you have experience in production of Alprazolam?

 

[riderofapocalypse]

Experience yes, but its pain in the ass (nitrogen gas, urotropine etc.) and its better to find raw (which is hard, china deathrow/india big fines). Just ask your questions and i will try to clarify.

 

[experimentsci]

I am very interested in producing Alprazolam. But when you say, that this synthesis-route will not yield in Alprazolam, than I am interested to get a good working route.
My plan is to produce Alprazolam in big scales. Do you have any experience and a favourite synthesis-route for that?
Thank you a lot so far.

 

[riderofapocalypse]

yes, stick with chinese google patent provided by me in this topic, you just have to add 20% reaction time to these numbers .

Indian synth is bullshit, it will not provide nordiazepam.

 

[experimentsci]

Could you please send the patent again, I did not find it.
Thank you very much so far.

 

[wrinkledmost]

The Chinese patent: https://patents.google.com/patent/CN104130201B/en

Doesn't produce alprazolam, in the title of the patent it says it's for "alprazolam intermediate benzodiazepine thioketones"

If you follow steps 1 and 2 of the embodiments of the Chinese patent you get 7-chloro-5-phenyl-1H benzo[e][1,4]diazepin-2(3H)-one (nordiazepam)

Step 3 that requires the nitrogen protection just turns the nordiazepam ketone into a thione so step 3 produces:

7-chloro-5-phenyl-1H benzo[e][1,4]diazepin-2(3H)-thione

I'm not 100% sure on this so correct me if I'm wrong.

@experimentsci if you're having trouble with the solvent free creation of nordiazepam then use the Chinese patent I listed and do steps 1 and 2 of the embodiment