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Polymorphism of Alprazolam (Xanax) and Its Relation to Possible Polymorphs of Intermediate, Nordiazepam. Publication Review and In-House Experiment

I have uploaded a PDF of the publication, the purpose of this post is to review some key information that pertains to the clandestine chemist in the field of benzo synthesis. I conducted a series of experiments today which involved the recrystilization of nordiazepam in methanol & ethanol. I attempted a medium size batch of a popular synthesis route for alprazolam, but focused on the nordiazepam synthesis portion.

Part I: Small report on todays batch, which involved an issue that had to be troubleshooted.

Method of synthesis:
"Chloro acetyl chloride (316 mL) was added drop wise to a 500 mL beaker containing 2-amino-5-chloro benzophenone (62.68 g). This addition occurred at room temperature and after 45 minutes, all 2-amino-5-chloro benzophenone dissolved. After completion of the reaction, NH4OAc (62 g, 3 mmol) and K2CO3 (113.43 g, 3 mmol) were added to the mixture at room temperature under solvent-free condition and stirred for 2.5 h. After 2.5 hrs, 100 mL of water was added and the solids were filtered off. The solids were then triturated in a 2L flask with water, filtered and dried in a vacuum oven at 60 C for 3 hours."

The original procedure is very small scale (they start with .213 g of 2-amino-5-chloro benzophenone and 1.2 mL of chloro acetyl chloride. Now, the point of error I made (denoted in bold). I added the NH4OAc first and no issues occurred. When I added the K2CO3, the issues began. The original procedure did not mention that the addition of the K2CO3 should be done SLOWLY (I didn't add it all at once, but I should have added it slower). When the K2CO3 was added, the reaction started to boil and produce white vapor. Unfortunately, it formed black sludge. I thought the synthesis was done for, but nonetheless I carried forward. After the water wash, I ended up with a light to dark brown, semi-crystalline material. My first thought was to recrystallize.

Part II: Utilizing the attached publication to assist in trouble shooting

LogP of alprazolam: 2.37
LogP of nordiazepam: 3.21

From the publication:

"Plate-shaped crystals of anhydrous alprazolam (known as form I or b-alprazolam, melting point: 224–228C) are obtained by recrystallization from dry methanol while a dihydrate is formed when this recrystallization recrystallization occurs in presence of not well-dried methanol. On the other hand, desolvation of the acetonitrile solvate leads to the formation of an unidentified polymorph. In a related study, the single crystal structures and powder diffraction data of form I, the dihydrate, and another polymorph (form II or a-alprazolam, as they called) of this drug. These authors reported that form II can be obtained from recrystallization in ethylacetate and form I from flash cooling of an isopropanol solution."

Part III: Solving the issue

The plan: I was going to recrystallize my dirty nordiazepam with methanol and ethanol (samples A1 and B1). In order to fix the color, I prepared two recrystalizations (methanol and ethanol) and also added activated carbon (samples A2 and B2). Once I found a combo I liked, I utilized the method for a medium recrystilization (sample C1) and a large recrystilization (C2). I could perhaps post photos of the samples tomorrow. All samples were allowed to cool at room temp and then were placed into the freezer for 10 minutes, which were then filtered and dried.

Sample A1 (methanol recrystilization):
-Nordiazepam (300 mg) was placed in an Erlenmeyer flask and hot methanol was added until complete dissolution.
-after final filtration, this sample was light red and consisted of short needle like crystals.
-270 mg was recovered (90% recovery)

Sample A2 (methanol recrystilization w/ activated carbon via hot filtration)
-Nordiazepam (300 mg) was placed in an Erlenmeyer flask and hot methanol was added until boiling occurred, 15% w/w of activated carbon was added to the boiling solution. Hot filtration was performed afterwards and then placed in freezer,
-after final filtration, this sample was light yellow and consisted of short needle like crystals.
-240 mg was recovered (80% recovery)

Sample B1 (ethanol recrystilization)
-Nordiazepam (300 mg) was placed in an Erlenmeyer flask and hot ethanol was added until complete dissolution.
-after final filtration, this sample was light brown and consisted of fibrous like crystals.
-270 mg was recovered (90% recovery)

Sample B2 (ethanol recrystilization w/ activated carbon via hot filtration)
-Nordiazepam (300 mg) was placed in an Erlenmeyer flask and hot ethanol was added until boiling occurred, 15% w/w of activated carbon was added to the boiling solution. Hot filtration was performed afterwards and then placed in freezer,
-after final filtration, this sample was light yellow and consisted of short needle like crystals.
-240 mg was recovered (80% recovery)

My favorite sample & method: sample A2 (methanol recrystilization w/ activated carbon via hot filtration)
I was not a fan of the fibrous needles produced by utilizing ethanol

Sample C1 (medium sized methanol recrystilization w/ activated carbon via hot filtration)
-Nordiazepam (5 g) was placed in an Erlenmeyer flask and hot methanol was added until boiling occurred, 15% w/w of activated carbon was added to the boiling solution. Hot filtration was performed afterwards and then placed in freezer,
-after final filtration, this sample was light yellow and consisted of short needle like crystals.
-3.75 g was recovered (75% recovery)

This is now where I got cocky...

Sample C2 (large sized methanol recrystilization w/ activated carbon via hot filtration)
-Nordiazepam (20 g) was placed in an Erlenmeyer flask and hot methanol was added until boiling occurred, 20% w/w of activated carbon was added to the boiling solution. Hot filtration was performed afterwards and then placed in freezer,
-after final filtration, this sample was light yellow-brown and consisted of short needle like crystals.
-10 g was recovered (50% recovery), most was lost in the abyss of the black carbon RIP.

Summary: I still have 50 g of the crude nordiazepam, so I will stay at 15% w/w addition of activated carbon. I gotta say, Sample C1 looks incredible! Short, yellow, needle crystals. I will do this tomorrow.

Did I manage to produce polymorph X with EtOH and polymorph Z with MeOH? Cant say for sure (wish I had a DSC), but judging by the differences in crystal appearance (fibrous vs needle like), different polymorphs are likely!

I will be playing around with ethyl acetate and ACN recrystilizations as well.

EXTRAS:
I managed to convert 1.08 g of nordiazepam to .88g of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]- diazepin-2(3H)-one (final precursor to alprazolam!!

Hope you enjoyed and hopefully I can soon post a full report on the synthesis of alprazolam (large scale), starting from 2-amino-5-chloro benzophenone

I want there to be more clandestine production of alprazolam, since most are familiar with this substance compared to some obscure RC.

I will also start developing a sustained release lozenge for alprazolam and also a 24 hr transdermal patch in the near future.
 

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HerrHaber

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Thank you for sharing this insight as well as the publications, I have in plan to attempt this synthesis (or theese syntheses, rather) and of course alprazolam is in focus since it is much sought after. The preparative detail of slowly adding the carbonate is of great importance when approaching a larger scale. I made a promisse to my good self not to be involved in sedative synthesees since I'm much fond of their effects but as I come to age some wierd infantile thoughts like "why go to the M.D. when you can make em" appear. Asking for nordiazepam and do the rest is the too easy way to go but chemist needs refference materials. The parent benzophenone I also think shouldn't be impossible to get but idk the cost of it (I do have enough rethrosynthetic imagination to assume it's obtained by the F-C acylation of p-Cl-aniline with benzoyl chloride with anh. AlCl3 equimolar catalyst). Thank you for this high quality read I had.
 
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