What is wrong with the MDMA available today? - v2

[vash445]

/u/4DQSAR

Recently got a meh batch moonrock testing at UVIC and GYTD

Acetone wash ice cold acetone yielding not much or anything off it but a recrystallized batch from dry acetone approx. 75% of acetone and 25% of 99.X% ethanol. Methanol is banned in my state so harder to get. Recrystallized from table top cooling

Reports were fantastic MDMA.

Grain size maps guidelines 2-3mm, color Pure white sparkling so as described here.

Rest was decanted for crop 2 with added acetone liquid is currently 'honey" consistent color wise


, a 2-3mm range generally falls within the coarse sand to granule categories, depending on the specific scale used. Specifically, within the Wentworth scale (also known as the Udden-Wentworth scale) and Krumbein phi scale, the 2-3mm range is considered coarse sand to granule

In chemistry and materials science, grain size refers to the size of individual crystals or grains within a material, particularly in polycrystalline materials like metals and ceramics. It's a crucial property that significantly influences a material's mechanical, chemical, and physical behavior.
Elaboration:

Definition:
Grain size is the average diameter of the individual crystals (grains) that make up a polycrystalline material.

Importance:
Grain size affects various properties, including:
Strength: Smaller grain sizes generally lead to increased strength due to more grain boundaries that hinder dislocation movement.
Ductility: Larger grain sizes tend to increase ductility (ability to deform without fracturing).
Toughness: Grain size can influence a material's ability to resist fracture.
Other properties: Grain size also impacts properties like corrosion resistance, electrical conductivity, and thermal stability.
Factors influencing grain size:
Nucleation and growth processes: These processes during solidification or other material transformations determine grain size.
Annealing temperature: Heat treatments can affect grain size and distribution.
Alloying elements: The presence of other elements in a metal can influence grain growth.


. Good manufacturing practices (GMPs) apply to all, but the level of detail and documentation required increases with exposure and risk. In other words, the regulatory requirements for an investigational drug used in small early-phase trials, manufactured on a small scale without the need for multiple-batch reproducibility, is different than for investigational drugs used for larger, late-phase trials or commercial products (wherein batch sizes can be many orders of magnitude larger and are part of multiple-batch, routine manufacture).

PSD, or particle size distribution is important to determine as it affects drug efficacy, safety and manufacturability.


In the pharmaceutical industry, particle size distribution (PSD) is a measurement that describes the variation of particles in a drug according to their size. The importance of particle size in pharmaceutical development is evident through the various assessment paraments, for which PSD is the most significant. Measurement of PSD typically takes place with sieve analysis, laser diffraction, dynamic image analysis or dynamic light scattering.
The particles in a pharmaceutical product sometimes differ in measurement due to their shapes. For particles that are nearly perfectly spherical, their measurements use their diameter. Other ovoid or irregularly shaped particles might have both length and width measurements. While taking horizontal and vertical measurements provides the greatest accuracy, doing so is a more complex process than simply determining a diameter. Therefore, most measurements assume each particle is a sphere and report an approximate diameter only.


* Crushing MDMA via a mortar and physical action still leads to "meh mdma." However the product was milled down to a powder.

Importance of Particle Size Distribution in Pharmaceuticals

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Recrystallization from dH20 prior yielded amazing methlike shards that were flat blades, but meh MDMA. Recrystalized took months in water, in high humid area. But brittle product.

The large numbers of 3,4-methylenedioxy-N-methylamphetamine (MDMA) formulations encountered by the police and border security necessitates the need for safe, rapid and reliable tests to be performed on-site. Near-infrared (NIR) spectroscopy is a promising technique for on-scene illicit-drug detection because of its rapid analysis, non-invasive nature, broad scope to detect various substances, and small-sized sensors suitable for portable operation. The NIR spectrum of MDMA shows an intriguing, intense peak at ∼2000 nm that was found characteristic for MDMA within a large set of drugs and drug-related substances. Herein, we show that this peak can be attributed to water molecules of crystallization in the MDMA lattice. Drying experiments showed that both an anhydrous and hydrated form of MDMA·HCl exists with significantly different NIR spectra. At ambient conditions, the anhydrous form converted back to the hydrated form within 2 months. Our data analysis model was able to identify MDMA·HCl in mixtures of both forms. Assessment of seized casework materials showed that the majority of MDMA·HCl in The Netherlands is of the hydrated type. This is explained by the use of water-containing concentrated hydrochloric acid in the final conversion step of MDMA-base to the hydrochloride salt in clandestine laboratories. These findings provide insight in the challenges associated with NIR-based identification of drugs that may appear in various crystalline forms.

https://www.sciencedirect.com/science/article/pii/S2468170922000674

 

[vash445]

I llooked at the various syntheses and it appears that with the 'moonrock' MDMA, halogenation of the aromatic was the most commonly observed impurity.

But in all fairness, 'moonrock' does essentially mean nobody in the chain from producer to consumer can cut the stuff. In the 80s pill presses were hard to obtain and costly so those who made Doves (or whatever your favouroite was) had invested a considerable ammount in branding their product to keep up the value.

Then idiots would buy good pills, crush them, add a cut or just repress with less in each pill. So nobody really knew what they were getting and value collapsed. So someone has VERY cleverly solved this issue for now at least. SOMEONE will figure out how to adulterate moonrock...

"To the best of our knowledge, there are very few examples where a continuous-flow bromination has been developed that includes an in-line purification before telescoping into a subsequent reactor..."

Also please note, I understand this is norket via a-bromo (ketone) compounds or even potentially, B or y if you dig more. However, Conversion and yield were determined by

"1H NMR using 1,3,5-trimethoxybenzene as an internal standard Isolated yield." ...1,2,3-trimethoxybenzene to 1,3,5-trimethoxybenzene involves "Friedel-Crafts acylation" followed by a decarboxylation step then forward yields... well that isn't important here,

The importance here is for someone /anyone who doesn't know chemistry, and how it is related is that most reactions can sub bromo for iodo, etc. etc.

Anyways take a look at for reference

. _________ ________ proceeds via tricarbonyl(h6-1,2,3-trimethoxybenzene)chromium complex. Treatment of tricarbonyl(h6-1,2,3-trimethoxybenzene)chromium complex 1 with acetonitrile carbanion in THF and then with iodine followed by reduction of the nitrile function gives mescaline. Deprotonation of complex 1 at the C5 carbon with LiTMP followed by chlorination, bromation or iodation gives 5-chloro, 5-bromo or 5-iodo complexes, useful synthons in organic synthesis for the preparation of 1,2,3-trimethoxy-5-substituted derivatives, precursors of natural products. Hydrogenation of the nitrile 5 using a literature procedure [2g] gave me_ _ _ _ _ _ _ in 80% yield and in 66% overall yield starting from 1,2,3-trimethoxybenzene




Continuous processing is becoming increasingly attractive for the manufacture of medicines because it offers opportunities for faster process development and safer handling of hazardous reagents. (1) Over the past two decades, continuous-flow chemistry has become commonplace in both academia and industry and nowadays it pervades the whole process of research, from reaction discovery and optimization to scale-up and production of fine chemicals and active pharmaceutical ingredients. (2) The increasing interest in this field stems from the many advantages that synthesis in-flow can offer. Specifically, processes can often be made safer, greener, and more efficient when performed in continuous flow. These benefits are particularly apparent when working with hazardous materials, where the scalability of a process in a batch format can be problematic. (3,4) Flow chemistry also offers flexibility in reconfiguring reactors to adapt to changing manufacturing requirements. This is particularly useful in the context of personalized medicine, which leads to the production of a larger number of compounds but in relatively small amounts. In this paper, we demonstrate how flow chemistry can simplify the synthesis of norketamine (5), a pharmaceutically relevant metabolite of the antidepressant, ketamine (4). We take advantage of flow chemistry to minimize the risks of handling toxic reagents such as ammonia and molecular bromine on a kilo scale. In our experience, we found that the resultant crude mixture remained considerably colored following this protocol (an indication of bromine and/or its derivatives) and we were keen to develop a procedure that efficiently removed these contaminants. As such, several aqueous quench solutions were trialed."

A three-stage continuous-flow process for the synthesis of norketamine (5) is reported. Initially, α-bromination of the key precursor 1 was achieved with quantitative conversion using a CSTR that allowed the safe removal and quenching of the hydrogen bromide by-product. This process was demonstrated on a 0.89 kg/day scale. Next, the subsequent imination process was achieved in excellent yield, representing a rare example of the use of liquid ammonia in a continuous-flow reactor. It was then demonstrated that these processes can be linked via an in-line quench and purification with a liquid–liquid membrane separator. Finally, the last step in the synthesis of norketamine (5) was achieved on a 1.4 kg scale via the thermal rearrangement of the α-hydroxy imine 3 in a commercially available tubular flow reactor.

The product was not isolated but instead N-Boc protected for use in subsequent steps

See
Organic Process Research & Development
Cite this: Org. Process Res. Dev. 2022, 26, 4, 1145–1151

https://doi.org/10.1021/acs.oprd.1c00407

Copyright © 2022 American Chemical Society. This publication is licensed under


Published March 26, 2022 for more on telescopic (α-bromoketone)

At least how I read it.

 

[vash445]

"To the best of our knowledge, there are very few examples where a continuous-flow bromination has been developed that includes an in-line purification before telescoping into a subsequent reactor..."

Also please note, I understand this is norket via a-bromo (ketone) compounds. However, Conversion and yield were determined by

"1H NMR using 1,3,5-trimethoxybenzene as an internal standard Isolated yield." ...1,2,3-trimethoxybenzene to 1,3,5-trimethoxybenzene involves "Friedel-Crafts acylation" followed by a decarboxylation step then forward yields... well that isn't important here,

The importance here is for someone /anyone who doesn't know chemistry, and how it is related is that most reactions can sub bromo for iodo, etc. etc.

Anyways take a look at for reference

. Mescaline synthesis via tricarbonyl(h6-1,2,3-trimethoxybenzene)chromium complex. Treatment of tricarbonyl(h6-1,2,3-trimethoxybenzene)chromium complex 1 with acetonitrile carbanion in THF and then withiodine followed by reduction of the nitrile function gives mescaline. Deprotonation of complex 1 at the C5 carbon with LiTMP followed by chlorination, bromation or iodation gives 5-chloro, 5-bromo or 5-iodo complexes, useful synthons in organic synthesis for the preparation of 1,2,3-trimethoxy-5-substituted derivatives, precursors of natural products. Hydrogenation of the nitrile 5 using a literature procedure [2g] gave mescaline in 80% yield and in 66% overall yield starting from 1,2,3-trimethoxybenzene




Continuous processing is becoming increasingly attractive for the manufacture of medicines because it offers opportunities for faster process development and safer handling of hazardous reagents. (1) Over the past two decades, continuous-flow chemistry has become commonplace in both academia and industry and nowadays it pervades the whole process of research, from reaction discovery and optimization to scale-up and production of fine chemicals and active pharmaceutical ingredients. (2) The increasing interest in this field stems from the many advantages that synthesis in-flow can offer. Specifically, processes can often be made safer, greener, and more efficient when performed in continuous flow. These benefits are particularly apparent when working with hazardous materials, where the scalability of a process in a batch format can be problematic. (3,4) Flow chemistry also offers flexibility in reconfiguring reactors to adapt to changing manufacturing requirements. This is particularly useful in the context of personalized medicine, which leads to the production of a larger number of compounds but in relatively small amounts. In this paper, we demonstrate how flow chemistry can simplify the synthesis of norketamine (5), a pharmaceutically relevant metabolite of the antidepressant, ketamine (4). We take advantage of flow chemistry to minimize the risks of handling toxic reagents such as ammonia and molecular bromine on a kilo scale.


In our experience, we found that the resultant crude mixture remained considerably colored following this protocol (an indication of bromine and/or its derivatives) and we were keen to develop a procedure that efficiently removed these contaminants. As such, several aqueous quench solutions were trialed."

A three-stage continuous-flow process for the synthesis of norketamine (5) is reported. Initially, α-bromination of the key precursor 1 was achieved with quantitative conversion using a CSTR that allowed the safe removal and quenching of the hydrogen bromide by-product. This process was demonstrated on a 0.89 kg/day scale. Next, the subsequent imination process was achieved in excellent yield, representing a rare example of the use of liquid ammonia in a continuous-flow reactor. It was then demonstrated that these processes can be linked via an in-line quench and purification with a liquid–liquid membrane separator. Finally, the last step in the synthesis of norketamine (5) was achieved on a 1.4 kg scale via the thermal rearrangement of the α-hydroxy imine 3 in a commercially available tubular flow reactor.

The product was not isolated but instead N-Boc protected for use in subsequent steps

See
Organic Process Research & Development
Cite this: Org. Process Res. Dev. 2022, 26, 4, 1145–1151

https://doi.org/10.1021/acs.oprd.1c00407

Copyright © 2022 American Chemical Society. This publication is licensed under


Published March 26, 2022 for more on telescopic (α-bromoketone)

At least how I read it.

I also wonder, we all know that ketone can be made via an Enamine formation followed by oxidation. Pain in the rear due to single, double and triple octive oxygen ( of something like that. IE mechanical O2 vs synthesis of O2.. and with bromine, Br2 etc, very not fun to play with.. Instead I do also wonder if, The Bromination of Enaminones with N-Bromosuccinimide instead of the Enamine could be at play instead. Enaminones (which are nitrogenous compounds with a carbonyl group adjacent to a carbon-carbon double bond and an amine group) can be reduced to enamines or ketones

An efficient method for the preparation of β-amino-α,β-unsaturated carbonyl compounds is demonstrated. Bench-stable sodium 3-oxo-enolates were prepared from carbonyl compounds, and reacted with amines in the presence of an acid and a desiccant...3-oxo-enolates are specific types of enolates where the carbonyl group (C=O) is located at the 3-position of a ring or in a molecule. APPAN is 3-Oxo-2-phenylbutanenitrile. Methyl 3-oxo-2-phenylbutyrate (MAPA) is also recently circulating precursor a precursor of amphetamine and methamphetamine. MAPA has a hybrid chemical structure of acetoacetic acid ester and it's main ketone. Acetoacetic acid ester is de-esterified and decarboxylated to give the ketone by heating under acidic conditions; therefore. Considering that ethyl 3-oxo-2-phenylbutyrate (EAPA), methyl 3-oxo-4-phenylbutyrate (MGPA), and ethyl 3-oxo-4-phenylbutyrate (EGPA) have the same chemical features as MAPA, it is safe to assume these also exist as an MD version somewhere


So there is little doubt an MD version of 3-oxo-enolates is around. The 3-oxo-enolate can exist in two forms: the keto form (the ketone) and the enol form. The enol form has a double bond between the alpha-carbon and the carbon adjacent to the ketone, and an alcohol group attached to the alpha-carbon. If an enolate is formed from a ketone and reacts with another carbonyl (like a ketone), the resulting product is a 1,3-diketone or 1,3-ketoester if the second carbonyl was an ester. One could go many different routes to Ketones, For example, Bromine will react with the enol form, adding a bromine atom at the carbon bearing the enol double bond. This process can happen twice, resulting in a dibromo ketone for example I think? Solid and liquid 1,3-diketones and b-keto esters can be successfully and selectively brominated with NBS at room temperature with no solvent



Or that Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis is interesting in that


Additionally, the allyl alcohols, synthesized from the monoterpenoid citronellal (6a) and the commercially used fragrant helional (6b), could also be functionalized under the manganese catalyzed hydroamination conditions and the products 7a,b were isolated in high yields, and moderate diastereoselectivities (Scheme 2c). Additionally, cytisine 2zh could be hydroaminated with the allyl alcohol derived from helional (6b), yielding the conjugate 7c in moderate 50% yield.

I imagine the Cyclization breaking could be opened, but I'm not sure though, I'm sure those that know, would know what I'm alluding to. IE ring opening of the epoxides, Heck, Suzuki, and Olefin Metathesis Reactions but i'm probably more wrong here then uptop.

Of course, there is a DOI for a process leveraging the chiral pool has been developed to access enantiomers of both MDA and MDMA. Critical aspects of the process were identified and include utilization of freshly prepared Grignard solution (3) with rapid addition of this solution to aziridine 6 and subsequent shortened reaction times. Characterization data have also been provided to enable in-process monitoring for key reaction intermediates as well as critical and noncritical byproducts with consideration of their impact on final product quality

I also removed a lot of information to obey the rules here. And take my thoughts with a grain of N-BOC MDMA.hcl salt this is probably way out of my wheelhouse but, I feel there could be some valid in sites here