Author Topic: Lefetamine via its amino-alcohol? (Read 280 times)

carl_nnabis · « **on:** June 11, 2012, 12:34:12 PM »

I thought about this some time ago, and when my internet connection was lost like for two hours recently I saw through my molecule-drawings (yeah on paper, do not even have some chemsketchy-like stuff

), and noticed there was that really straight lefetamine synthesis via the aminoalcohol as intermediate i forgot about.

Benzoin is a lot more avaible and a lot cheaper than "deoxybenzoin", and it seemed always like some trouble to remove the hydroxyl group without touching the carboxyl first, so why not aminate first to get rid of that problem? For me it is to aquire dimethylamine (as salt not solution to get the free anhydrous amine in alcohol) readily, otherwise I had tried it yet for sure! Its one of the few stimulants left that I really want to try out some day.

Just imine formation with benzoin and dimethylamine in alcohol and reduction of the formed imine by method of choice to get something which could be called "lefetadrine" or using more proper terms
"RS-ß-hydroxy-N,N-dimethyl-1,2-diphenylethanamine"
This racemic aminoalcohol could be the already treated to separate enantiomers... but it has four instead lefetamines just two and enantiomeric resolution is always a bitch to do so impractical at this point.
So we could take this intermediate and reduce it with any of the popular methods, birch, red phosphorus and iodine, halogenating/esterify the alcohol then CTH, etc etc.'
And then one could go on and resolve its enantiomers, the unwanted one can also be used for preparation of some more "deoxybenzoin"
What do you think about this one? Except the needed resolution afterwards it seems feasible and really straight I think?
maybe one day when I run out of other interesting projects ...

carl_nnabis · « **Reply #1 on:** June 11, 2012, 10:21:23 PM »

The first redirect on wikipedia leads to another interesting compound:
http://en.wikipedia.org/wiki/MT-45
The racemate is potent as morphine!
And benzoin, piperazine and cyclohexanone would be well suited starting materials!
just prepare n-cyclohexylpiperazine from piperazine monohcl and cyclohexanone, or O-tosylcyclohexanol (or cyclohexylbromide for a less good leaving group), then the same story as above (imine formation and reduction)! But no resolution needed!
But i dont know if it has stimulant properties, neither do i care about when it said to be potent like morphine

Edit:
Just found this, look at this i read through it at the moment...
http://www.patentstorm.us/patents/3957788/fulltext.html

carl_nnabis · « **Reply #2 on:** June 12, 2012, 06:37:51 AM »

its not really hard to get, everything except dimethylamine can be had OTC and i wont get dimethylamine either

For example 2 mol benzaldehyde undergo thiamine-HCl catalysed condensation to give 1 mol benzoin, piperazine is used as dewormer, and cyclohexanone/cyclohexanol is for sure in some OTC solvent. just look through the material safety data sheets of some products, I bet there are some.
There is no excuse for anybody of you other guys not to try this out

edit: thiamine-hcl is more commonly known as Vitamine B1

edit2: dimethylamine can of course also be made, same story as with methylamine just double the amount of formaldehyde, but its also a gas i am not willing to work with it when it could be simply replaced with piperazine

atara · « **Reply #3 on:** June 12, 2012, 07:54:05 AM »

Short alkyl esters can mono-acylate piperazine, which allows you to add each substituent to piperazine in sequence. I don't know how the rate of the second alkylation compares to the first -- it could be unnecessary.

On the subject of lefetamine, the commonly-mentioned but rarely-successful route is a Stevens rearrangement on the tantalizingly simple dimethyl dibenzyl ammonium. Unfortunately the relevant hydrogen is not very acidic (pKa ~30 in DMSO), so typical bases won't work. I was thinking -- sodium isopropoxide? "Easy" to prepare -- sodium (it's not potassium!) in isopropanol -- and not much more nucleophilic than the popular (but needing-to-be-special-ordered) KOtBu.

The same idea could also be applied with, e.g., 1-acetylpiperazine and benzyl chloride.

Cyclohexanone/ol: I don't know any products that contain it, I'm afraid. Adipic acid can bee sourced and converted to cyclopentanone. The longer pimelic acid should generate cyclohexanone in the same reaction and can be synthesized from salicylate which is kind of a pain... despite these reactions being well-characterized, it seems like there should be something easier. Maybe you can just use thujone and hope for the best? Hehe...

carl_nnabis · « **Reply #4 on:** June 12, 2012, 02:33:24 PM »

I cannot clearly see how the stevens rearrangement is related to this maybe i dont get it? To get dimethylamine or why? Please tell me why i should use it when it can be so much simpler?
Dimethylamine is listed as precursor for chemical weapons here so theres no chance to get it anyway, so i can forget about the subject lefetamine if I dont want to mess around with formaldehyde.
That you have to use the monohydrochloride of piperazine to dont get a dialkyl/acylated product was mentioned, way easier to form the mono-hcl than acetylpiperazine in my opinion.
take a look at benzylpiperazine synthesis, its the usual way to do this.
You cannot find a product containing cyclohexanon? i think you may have to look harder because i know of several products here, usually mixed with cyclohexanol. Its just a harmless solvent albeit its used in synthesis of several dissociatives, but these arent really commonly homebaked since the chinese cover any desire.

atara · « **Reply #5 on:** June 13, 2012, 12:33:45 AM »

Dimethylamine can be obtained from the decarboxylation of sarcosine, or the similar decomposition of creatine. Similarly tetramethylammonium can be obtained from betaine.

However, I don't know that it is controlled; I can't think of any drug that uses dimethylamine as a precursor, other than lefetamine -- certainly not DMT!

carl_nnabis · « **Reply #6 on:** June 13, 2012, 12:48:23 AM »

This is for sure of more use in the other topic I have posted five minutes later than you!

fresh1 · « **Reply #7 on:** June 14, 2012, 12:32:36 AM »

please correct me if I am wrong (fair chance

) IIRC cant diethylamine be made the same way as methylamine?

Aren't the dimers and trimers produced related to the temperature the rxn is carried out at...with temps over 106c producing varied amounts of all 3?

Although I have no idea how you would seperate them

Anyone? I'm quite curious as to how this would be done

atara · « **Reply #8 on:** June 14, 2012, 03:23:10 AM »

With regard to methylamine, there are several ways to produce it: hexamine decomposition (which produces no dimethylamine), acetamide decomposition (can be modified to produce ethylamine, aniline, etc, but no dialkylamines), reduction of nitromethane (no dialkylamines for obvious reasons), reductive alkylation of ammonia (uses formaldehyde, produces a mixture of products), transfer alkylation of ammonia (produces multiply-alkylated products quite easily and iirc prefers trimethylamine), or glycine decarboxylation (can be modified to sarcosine for dimethylamine).

For many purposes nitromethane is simply reduced in situ by the amalgam used. Nitromethane is easier to work with and easy to source.

fresh1 · « **Reply #9 on:** June 14, 2012, 09:07:43 AM »

Quote

acetamide decomposition (can be modified to produce ethylamine, aniline, etc, but no dialkylamines)

hey atara would DMA (dimethylacetamide) be able to substiute for DI methylamine?

atara · « **Reply #10 on:** June 15, 2012, 06:54:33 PM »

Dimethylacetamide hydrolysis produces dimethylamine, yes.

However, I don't think a Leuckart-type reaction will proceed with DMF, much less DMA -- indeed, Leuckart reactions are often performed in DMF, which should highlight the inertness of DMF towards such a reaction. The nitrogen atom in dimethylamides is sterically hindered and not very nucleophilic. So you'd have to hydrolyse it, which means refluxing in sulfuric acid for a long time.

carl_nnabis · « **Reply #11 on:** June 17, 2012, 04:56:31 PM »

Quote from: atara on June 13, 2012, 12:33:45 AM

However, I don't know that it is controlled; I can't think of any drug that uses dimethylamine as a precursor, other than lefetamine -- certainly not DMT!

uhm.. i think you misunderstood a bit, i meant in my country (germany) its monitored... not as a drug-precursor, but as a chemical weapon precursor, not listed, but your supplier can fuck your ass if thats what he wishes to do

when this 19 year old kid died in 2007 while he recrystallized his homemade fentanyl (he was drunk in the lab^^), no one blamed the chemicals, only his irresponsibility... (he was a former science contest winner

)

atara · « **Reply #12 on:** June 17, 2012, 06:09:16 PM »

Dimethylamine from formamide and ammonium chloride? I don't need dimethylamine, as I don't intend to pursue this... but it sounds interesting.

Sydenhams chorea · « **Reply #13 on:** June 18, 2012, 12:32:38 PM »

Quote from: carl_nnabis on June 12, 2012, 06:37:51 AM

its not really hard to get, everything except dimethylamine can be had OTC and i wont get dimethylamine either
For example 2 mol benzaldehyde undergo thiamine-HCl catalysed condensation to give 1 mol benzoin, piperazine is used as dewormer, and cyclohexanone/cyclohexanol is for sure in some OTC solvent. just look through the material safety data sheets of some products, I bet there are some.
There is no excuse for anybody of you other guys not to try this out
edit: thiamine-hcl is more commonly known as Vitamine B1
edit2: dimethylamine can of course also be made, same story as with methylamine just double the amount of formaldehyde, but its also a gas i am not willing to work with it when it could be simply replaced with piperazine

Can you provide refs for the thiamine-catalysed condensation of benzaldehyde? Messing around with cyanide in the classic benzoin condensation is not an option, but I guess benzoin can also be bought.
Any refs handy on the preparation of N-cyclohexylpiperazine? This MT-45 looks worth a try.

edit:
deoxybenzoin from benzoin 80-84% yield using Sn/HCl:
http://www.orgsyn.org/orgsyn/prep.asp?rxntypeid=231&prep=CV5P0339

Quote

Reduction of benzoin by

zinc dust and acetic acid,
E. P. Kohler and E. M. Nygaard, J. Am. Chem. Soc., 52, 4133 (1930)

and by hydrochloric acid and granulated tin
J. S. Buck and S. S. Jenkins, J. Am. Chem. Soc., 51, 2163 (1929)
I. Allen and J. S. Buck, J. Am. Chem. Soc., 52, 310 (1930)

or amalgamated powdered tin
O. A. Ballard and W. M. Dehn, J. Am. Chem. Soc., 54, 3970 (1932)

has been reported.

carl_nnabis · « **Reply #14 on:** June 18, 2012, 10:45:21 PM »

thank you exactly THIS paper was what floated around my mind, as only convenient way to go from benzoin to desoxybenzoin!

I have one reference with a really good experimental part here about vitamin B1 catalysed benzoin formation, but its on german... Can translate the essential
http://forum.lambdasyn.org/index.php?PHPSESSID=a8fa60d8bb9d962b886256f62bba0822&topic=1340.0
1g Thiamine-HCl is dissolved in 2ml dH2O in a 25ml RBF, then 8ml 95% ethanol were added. To this, 3ml of a solution of 2M NaOH, are added during ~2min.
The solution turns intense yellow on addition, but faded away on standing.
4ml benzaldehyde are added, and the mixture under stirring mildly refluxed for 75 minutes. After that time, upon cooling, the benzoin will precipitate.

To the piperazine + cyclohexan(ol/ol) -> cyclohexylpiperazine thing... unfortunately i dont have anything about this, but a look in nicodems BZP synthesis in rhodiums archive may will help you clarifie?

Sydenhams chorea · « **Reply #15 on:** June 22, 2012, 12:59:30 AM »

Quote from: carl_nnabis on June 18, 2012, 10:45:21 PM

To the piperazine + cyclohexan(ol/ol) -> cyclohexylpiperazine thing... unfortunately i dont have anything about this, but a look in nicodems BZP synthesis in rhodiums archive may will help you clarifie?

There is an interesting route in Chem. Pharm. Bull. (1988) 36(10) 3948-3954 (attached). They reduce the imine from pyrrolidinocarbonylmethylpiperazine and 3,4,5-trimethoxybenzaldehyde with HCOOH (an application of the Leukart-Wallach reaction). Perhaps this could also be applied for cyclohexanone and piperazine:

Quote

Typical Procedures of Method B-1-(Pyrrolidinocarbonylmethyl)-4-(3,4,5-trimethoxybenzyl)piperazine Di-
fumarate (4p): 3,4,5-Trimethoxybenzaldehyde (5.0 g) and 1 (5.0 g) were melted in an oil bath at 120 °C and formic
acid (2.0 ml) was added dropwise. The mixture was stirred for 45 min under heat, and then allowed to cool to room
temperature. The mixture was diluted with EtOH (40 ml) and fumaric acid (6.0 g) in EtOH (40 ml) was added to the
solution. The precipitated solid was collected and recrystallized from MeOH to give 4p (8.0 g).
Compounds 4j-o and 4q-v were obtained in the same manner as described for 4p. The yield, melting point and
elemental analysis data are given in Table III

Let's dig up these refs and hope to shed some more light on the pharmacology of MT-45, preferentially the therapeutic index:

^ Natsuka K, Nakamura H, Uno H, Umemoto S (December 1975). "Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1". Journal of Medicinal Chemistry 18 (12): 1240–4. DOI:10.1021/jm00246a014. PMID 1195277.

^ Nakamura H, Shimizu M (May 1976). "Comparative study of 1-cyclohexyl-4-(1,2-diphenylethyl)-piperazine and its enantiomorphs on analgesic and othe pharmacological activities in experimental animals". Archives Internationales De Pharmacodynamie Et De Thérapie 221 (1): 105–21. PMID 962421.

carl_nnabis · « **Reply #16 on:** June 22, 2012, 07:48:44 PM »

thank you for the pharmaceutical data about this, would be so awesome if it turns out this is an abusable compound!

just considered how easy it is made! Really only out of freely available precursors!
Ok. agreed its a long road to go, but hey even more straighter in shorter time than poppy growing for precursor use for opiates in small amounts, fuck yeah^^!
Safer too, even the eyeballing wont kill experienced ones, but way more unsuspicious like pethidine (never tried it, nearly pulled off the market here) or fentanyl precursors are... i mean baking aroma or if you have to make it because of restrictions, then you will definitely know better how this is done than me (I really feel sorry for you UA and australia dudes... your gov´s and their stupid nobrainer-laws are fucked up pretty hard

)
in europe you would get benzaldehyde in every country i know of, sometimes even 98% pure, as baking aroma, in stores, no not even over the counter, its more like OTS, off the shelves!!!

then simply dewormer, not so easily found but in small amounts usual nonsuspicious, dont go on and buy kilos of that shit, that will definitely raise some suspection! they forbid like 5-10 piperazines mainly over the last 15 years, and other RCs too just because they were free sold as headshop products, in other countries the same.

just imagine a store clerk without any knowledge hears you to buy a kilo "piperazine", would sound like buying a kilo "methylendioxy" when the store clerk assumes you have a kilo "methamphetamine" and put that simply together for 2 kilo "methylendioxymethamphetamine", isnt it?

pretty funny if he replies "would you like to have your kilo of benzyl to this then readily sir?"

I am really not a fan of the leukart-wallach, its too impractical... You have to use pressure, anhydrous conditions and even then the yield could be low...
Applied to cyclohexanol/-on simply piperazine and phenylchloride/bromide in polar aprotic solvent of choice, use what is more available: DMF, DMSO, are really easy to find i think, the run the reaction at roomtemperature at least a half day i would advise...can also bee a very high yielding one if run longer (as seen with tryptamine^^) you definitely know what i mean there

Simply i doubt a mono-hydrochloride made accordings to nicodems procedure will not work here too

carl_nnabis · « **Reply #17 on:** June 26, 2012, 10:15:14 PM »

I had an interesting idea... OH-group reduced using Sn/HCl, then or before that yeast reduction on the remaining ketone, to enantiopure "d-desoxybenzoinol" tosylation, and replacement with dimethylamine or 4-cyclohexylpiperazine for desired compound...
i have never tosylated anything, only hydrolyzes some grams TsCl and obtained wonderful pyramidish crystals of the acid i need for another thing but it looks its use is no problem at all it will not heavier react with a mild base as TEA or pyridine during tosylation that it did using Na2CO3 what i used to hydrolyze it obviously

and the smell is also not awful like someone states, its sweet and nasty but not overwhelming or strong. i think its a pretty cool replacement for halogenating any alcohol

Edit: D´Oh! I corrected the

Quote

using Na2SO3 what i used to hydrolyze

part because i used Na2CO3 of course

Sydenhams chorea · « **Reply #18 on:** June 27, 2012, 10:17:25 PM »

Quote from: carl_nnabis on June 22, 2012, 07:48:44 PM

I am really not a fan of the leukart-wallach, its too impractical... You have to use pressure, anhydrous conditions and even then the yield could be low...
Applied to cyclohexanol/-on simply piperazine and phenylchloride/bromide in polar aprotic solvent of choice, use what is more available: DMF, DMSO, are really easy to find i think, the run the reaction at roomtemperature at least a half day i would advise...can also bee a very high yielding one if run longer (as seen with tryptamine^^) you definitely know what i mean there

It's a variation of the Leukart-Wallach reaction, as you see HCOOH at 120°C is able to reduce the imine, it doesn't look too harsh or messy at first sight the way it is stated in the patent.

Author Topic: Lefetamine via its amino-alcohol? (Read 280 times)

carl_nnabis

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