Alprazolam (Xanax) synthesis. Small scale.

nbnbbnryrtyrt

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Is there any simple way to synthesize 2-Amino-5-chloro benzophenone or is it sold anywhere?
 

KokosDreams

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Agilent1100DAD

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I'd be interested in hearing about a report too
KokosDreamsJust 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
 

Agilent1100DAD

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Hey guys; I’ve done a similar synthesis and I’ve successfully produced about 50 g of diazepam. That was a while ago but now have enough precursor and solvents to produce about 80 g of alprazolam.

2-Amino-5-chloro benzophenone is readily available on sigma aldrich. It’s dirt cheap. I’ll post some photos of my diazepam synthesis.

Im new to this forum but have a lot of experience in general synthesis, analytical chemistry and drug delivery system development. My last company had a DEA schedule I & 3 research and manufacturing license, so I believe I have some knowledge I would like to share with the members here in due time. The following photos are from the diazepam synthesis. That was my first time doing it so the yield was low (60%) and the purity was sub-standard (95%) before re-crystallization. Purity was confirmed via LC-MS and structure confirmed via ATR-FTIR
 

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jarredreyes0303

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Hey guys; I’ve done a similar synthesis and I’ve successfully produced about 50 g of diazepam. That was a while ago but now have enough precursor and solvents to produce about 80 g of alprazolam.

2-Amino-5-chloro benzophenone is readily available on sigma aldrich. It’s dirt cheap. I’ll post some photos of my diazepam synthesis.

Im new to this forum but have a lot of experience in general synthesis, analytical chemistry and drug delivery system development. My last company had a DEA schedule I & 3 research and manufacturing license, so I believe I have some knowledge I would like to share with the members here in due time. The following photos are from the diazepam synthesis. That was my first time doing it so the yield was low (60%) and the purity was sub-standard (95%) before re-crystallization. Purity was confirmed via LC-MS and structure confirmed via ATR-FTIR
hello1321sheesh brother thats some fancy looking equipment ! you just do this as a hobby ? would love to be friends, i grow mushrooms and weed maybe we can share products and chat it up. feel free to message me
 

G.Patton

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Hey guys; I’ve done a similar synthesis and I’ve successfully produced about 50 g of diazepam. That was a while ago but now have enough precursor and solvents to produce about 80 g of alprazolam.

2-Amino-5-chloro benzophenone is readily available on sigma aldrich. It’s dirt cheap. I’ll post some photos of my diazepam synthesis.

Im new to this forum but have a lot of experience in general synthesis, analytical chemistry and drug delivery system development. My last company had a DEA schedule I & 3 research and manufacturing license, so I believe I have some knowledge I would like to share with the members here in due time. The following photos are from the diazepam synthesis. That was my first time doing it so the yield was low (60%) and the purity was sub-standard (95%) before re-crystallization. Purity was confirmed via LC-MS and structure confirmed via ATR-FTIR
hello1321You can sell them via BB market, if you want. Also, can get Manufacturer status. Don't hesitate to write me in PM, I'll help you.
@jarredreyes0303 You also very welcome!
 

G.Patton

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yea was talking with someone about opening a vendor shop , do you sell your results or would you send sample to give feedback ?
jarredreyes0303>>>do you sell your results or would you send sample to give feedback ?
What do you mean? Which results? I suggest to sell your product in BB marketplace.
 

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Hydrazine, seriously? You realize how dangerous that is right? Just saying, maybe a warning to everyone would be helpful
 

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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.

UkF8JTreqX
 
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jarredreyes0303

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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.

hello1321good stuff brother very impressive work !
 

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Alright guys I redid the first step of the synthesis (nordiazepam synthesis) but scaled up x10. I got about 60% yield this time.

Issues I had which lead to lower yield:

1. during the vacuum filtration step, my fritted filter was letting product through so I had to switch and re filter everything.

2. I added 10 mL of chloroacetyl chloride instead of 12 mL; I was luckily able to add the last 2mL towards the end of the 2.5 hr mark.

*I also will do a triturarion in a flask next time, post vacuum filtration wash; perhaps with a solvent in which nordiazepam is insoluble in

Going for a bigger run next week and then continuing on with the rest of the procedure.

First run was .23g, this run was 2.3g and the next will be 20g. Will keep you guys posted and will write a report with videos once Im done with the full synthesis
 

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Agilent1100DAD

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@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.
 

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Agilent1100DAD

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@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.
hello1321Forgot to add the photo for Part I Batch 003, just to compare colors.
 

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Hank Schrader

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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.
 

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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.
Hank SchraderExcellent, thank you very much for the cyclohexane advice. Will try this out once my new shipment of chloroacetyl chloride arrives.

XYv1KQbciV

Now for your second suggestion (methanol with urotropine), are you referring to the cyclization step in part I (after the addition of the chloroacetyl chloride) or part III?
 

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Hey G.Patton after lurking around the forums herre I finally came to the point were I told myself "I'm doing this" Yes yes for the yeild, however it's more less for me to just see if I can do it with how far I've come in self learning chemistry, I get that some of the others may say this is easy and maybe to some cool, for me, I want to ask and before doing this I firstly wanted to ask you my man, Is and or are there any specific relations, timings, things to note, and or semi simplicities that could be added kr reworded as well as things to note that are absolutely important things to keep in mind before during and after this whole process? Could you or someone be so kind as to either mentor or help guide as I walk though this process? I of course am working on certain key things that must be got (I don't believe details need explaining those things since making something from nothing isn't going to produce a finished product except disappointment. Jokes aside as I gather what is all needed know I do have some chem knowledge, If someone wants to say I'm stupid for trying this kr whatever being I'm not some master of the arts well if I fell over dead theb so Fucking be it, I doubt such a thing is going to happen but remaining safe and having an in-depth analysis and break down will really be appreciated thank you
 

G.Patton

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Hey G.Patton after lurking around the forums herre I finally came to the point were I told myself "I'm doing this" Yes yes for the yeild, however it's more less for me to just see if I can do it with how far I've come in self learning chemistry, I get that some of the others may say this is easy and maybe to some cool, for me, I want to ask and before doing this I firstly wanted to ask you my man, Is and or are there any specific relations, timings, things to note, and or semi simplicities that could be added kr reworded as well as things to note that are absolutely important things to keep in mind before during and after this whole process? Could you or someone be so kind as to either mentor or help guide as I walk though this process? I of course am working on certain key things that must be got (I don't believe details need explaining those things since making something from nothing isn't going to produce a finished product except disappointment. Jokes aside as I gather what is all needed know I do have some chem knowledge, If someone wants to say I'm stupid for trying this kr whatever being I'm not some master of the arts well if I fell over dead theb so Fucking be it, I doubt such a thing is going to happen but remaining safe and having an in-depth analysis and break down will really be appreciated thank you
Technerdfromhell™Hello.
Is and or are there any specific relations, timings, things to note, and or semi simplicities that could be added kr reworded as well as things to note that are absolutely important things to keep in mind before during and after this whole process?
You chose quite difficult synthesis. I would recommend you start from synthesis with video tutorial cuz you, with a high degree of probability, stuck somewhere by reason of luck skills and knowledge. I recommend this to avoid disappointment, loss of money and time. Every step of the synthesis is important and have own scene.
 

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Hello.

You chose quite difficult synthesis. I would recommend you start from synthesis with video tutorial cuz you, with a high degree of probability, stuck somewhere by reason of luck skills and knowledge. I recommend this to avoid disappointment, loss of money and time. Every step of the synthesis is important and have own scene.
G.PattonWoul you be kind as to aid rangrst starting spot? I was considering something along the A-Phip/a-pvp area? Did the DMT a f fsir amounts, I want to test myself but nothing way outy league. Any advice glassware, khsy plan, coxa leaves, pcp things like Thor but small scale I'll pay if some had any of thoughs?;
 

G.Patton

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Woul you be kind as to aid rangrst starting spot? I was considering something along the A-Phip/a-pvp area? Did the DMT a f fsir amounts, I want to test myself but nothing way outy league. Any advice glassware, khsy plan, coxa leaves, pcp things like Thor but small scale I'll pay if some had any of thoughs?;
Technerdfromhell™Start from a-PVP in case you are interested in this substance. I would recommend mephedrone. It is more interesting and kind drug. Its synthesis very easy, there is video tutorial.
 

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Just wanted to update you all; I managed to work some magic and get these incredible off white, long crystals. I’ve increased the starting material from .200 g to 20 g. I’ll be receiving a 5L reaction vessel tomorrow! Very excite



2AvCYJxBVE
2RPFnaSwoi
 

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Technerdfromhell™

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Just wanted to update you all; I managed to work some magic and get these incredible off white, long crystals. I’ve increased the starting material from .200 g to 20 g. I’ll be receiving a 5L reaction vessel tomorrow! Very excite



View attachment 9615View attachment 9613
hello1321When this is done maybe meet I buy 5 grams no l of them fro? You I have like 110$ to spend, I'm sure you're work y'all slot, I just want to test tiny bit Alt just to feel a professional finish product
I'd your do, x post tell me..or dose 10 &20 singles so I can do a wrote up.tty
 

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She has finally arrived…

Shes a 5L jacketed borosilicate glass reactor with an addition funnel, condenser, digital RPM controller for the overhead stirrer and temperature gauge. I have it connected to a water reservoir that’s connected to a poly science 1.5 HP chiller with a positive displacement pump and with a temp range of -70C to 300 C.

I am but a speck in an ocean of independent chemists, but this speck is LC-MS validated!!!!!
 

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jarredreyes0303

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cant wait for final results on this one haven't been so hopeful to see someone else succeed in a while. You got this man !
 
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