Phenylalanine to amphetamine or N-methylamphetamine;

Historically;

There are two routes that have been previously investigated and are documented on Rhodiums website and I am sure everyone reading this has seen. The first method uses Lithium Aluminium Hydride to reduce
phenylalanine to phenylalaninol. Then proceeds to protect the amine function, with a carbobenzyloxy (Cbz) group. p-Toluenesulfonyl chloride is then used to create the toluenesulfonate ester which when
reduced will remove the hydroxyl group aswell. Reduction with lithium aluminium hydride affords methamphetamine, all steps proceed with retention of configuration so if one started with D-phenylalanine one would end up with the required (S) enantiomer. The second route similarily starts by reducing phenylalanine to phenylalaninol this time using lithium borohydride, then protection of the amine
functionality with a tert-Butyloxycarbonyl(BOC) group forming a carbamate. Iodination of the hydroxyl group proceeds, and reduction of the iodo compound with sodium selectride reduces it to its parent
hydrocarbon. Triflouroacetic acid removes the BOC protection to leave amphetamine. Also this method proceeds with retention of configuration if you started with D-phenylalanine you would end up with the required (S) enantiomer.

Method 1
http://www.erowid.org/archive/rhodium/chemistry/amph.phenylalanine.html

Method 2
http://www.erowid.org/archive/rhodium/chemistry/amphetamine.phenylalanine.html

Now obviously those are not OTC, and require multi-step synthesis using some nasty chems. I was hoping to investigate some of the newer more relavent methods that are not the same as above. If anyone wants to add anything please feel free.

Phenylacetaldehyde from Phenylalanine

Phenylalanine can be treated with nitrous acid to produce phenyllactic acid, nitrous acid is produced from sodium nitrite and any mineral acid. Phenyllactic acid can then be treated with Lead tetra acetate (made with red lead oxide and glacial acetic acid) and will yield around 58% phenylacetaldehyde.

http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=bcsj1926&cdvol=9&noissue=1&startpage=8&lang=en&from=jnlabstract

Strecker degradation of phenylalanine with sodium hypophosphite should return a better yield of phenylacetaldehyde than the procedure above.
Also alpha methylation of phenylalanine as previously discussed after strecker degradation yields phenylacetone.

http://www.erowid.org/archive/rhodium/chemistry/p2p.strecker.html

With phenylacetaldehyde in hand one would proceed to gas with methylamine to create the schiffs base, which could be dripped into methyl magnesium iodide to produce a modest (40%+) yield of racemic methamphetamine.

Phenylalaninol from phenylalanine

Lithium Aluminium Hydride or Lithium Borohydride have been used in the past but the best option is today is Sodium Borohydride with nickel chloride or molybdenum trioxide to return the amino alcohol in 80%+ yields.

http://journals.tubitak.gov.tr/chem/issues/kim-99-23-2/kim-23-2-2-98058.pdf

From here I have seen much controversy, many loosely thrown accusations of reducing phenylalaninol with Hydroiodic acid to amphetamine. A poster named JustIce from WD was throwing around claims of reducing phenylalaninol to amphetamine with 80% yields using phosphorous acid and iodine with 2x excess at 120*C for 15 hours. He was actually quietly telling members via PM to do it, the results were verified via hp chromatography he said. A highly regarded member also wrote this at science madness, adding to the confusion;

"however the alcohol of phenylalanine, phenylalaninol, has been reduced to the alkane .....that claim I've made .......next!......solo"

To clear this up for good! Javas comments are true but.. Hydroiodic reductions refluxing phenylalaninol at anywhere under 125*C that are under 35 hours in duration WILL produce 1-phenyl-2-amino-3-iodopropane hydroiodide. Hydroiodic acid reductions ARE able to further dehalogenate 1-phenyl-2-amino-3-iodopropane to amphetamine but it will take around  a week at high temps under reflux, or in a sealed bomb that would have to be very hot!!! 58.4% Hydroiodic acid and red phosphorous refluxed at 125*C for 24 hours will produce 1-phenyl-2-amino-3-iodopropane in about 80-85% yield with traces of amphetamine! Decreasing the red-p and increasing the reflux to 35 hours will have no effect except the reaction rate will be decreased one third. So unless an extremely long hot reflux is employed or the use of a sealed bomb at high temps for a prolonged period of time is employed you will be producing 'JustIodo'. Hopefully Java can clear this up and explain what is actually necessary for complete reduction, but be certain that your average HI/I2 reaction wont cut it! (read the patent!) A much safer route would be to halogenate the amino alcohol to 1-phenyl-2-amino-3-iodopropane hydroiodide with an average hydroiodic acid/I2 reflux at about 110*C for seven hours to yield over 80%. Or with 48% hydrobromic acid in a sealed reaction vessel heated to 170*C for five hours to return 49% yield of 1-phenyl-2-amino-3-bromopropane hydrobromide.

Ref for iodo;
Ref for phenylalaninol reduction
Patent no;3193581

Ref for bromo;
Ring Cleavage of 1-Benzenesulfonyl-2-benzylethylenimine with

Hydrogen Bromide
http://pubs.acs.org/doi/abs/10.1021/ja01137a505

Reductive dehalogenation of 1-pheny-2-amino-3-halopropane

Then reductive dehalogenation, is carried out with LAH or raney nickel to yield amphetamine. N-methylation should proceed swiftly at this point!



 

I'm still thinking about Fester's mere refluxing of phen in sulfuric acid and ethanol for 3 hours to get it's ester. It is the same premise as all the outstanding patents on making the ester but it is still a little different which makes me wonder where UF pulled it out of his ass from. The patents have continuously adding ethanol while it distills off during the cook. Even the ones that do it under reflux are different. UF's way is a bit easier but I don't want to try it again if it doesn't work.

.........yes aziridines are interesting and no grilling necessary since i posted my findings long ago....at WD and with some help from other bee's, as this is how this works helping each other, the phenlalaninol is converted to the phenylanyl sulfate ester and once distilled in the presence of a concentrated NaOH solution 2-benxylaziridine  is produced, hence opening the ring via catalytic hydrogenation using Pd/C .....amphetamine is produced need only to find another way not needing a Parr Hydrogenator to do the deed......then methylation will give meth.......java/solo

I was debating whether to put this under Short Question or this thread so sorry to whoever thinks it belongs under Short Questions. I stumbled upon this at the hive. I tried to look into but didn't get very far. Seems hard to believe its would of gone unnoticed for over a decade so can someone more qualified then myself shoot it down real fast.

"OK, I'll give a general outline how to make benzedrine from phenylalanine:
1)reduce phenylalanine to phenylalaninol.
You can use NaBH4/H2SO4 to do this in one step, or you can make the acid chloride, which can be reduced to the alcohol.

2)reduce the phenylalaninol to benzedrine.
There are many ways, but in my opinion, the HI/red P reduction COULD be the way to go. The alcohol should be reduced in one step to the alkane, like described in the literature I gave in an earlier post. The amine is known to be stable, since ephedrine is reduced by HI/red P too.

Other ways to make benzedrine from phenylalaninol usually transform the alcohol to an halide, which is then reduced. But usually the amine needs to be protected for this, adding 2 steps to the sequence. These last steps are unnecessary if HI/red P is used. Lr/


Shaft
Junior Member   posted 09-01-98 12:14 PM"

As to the step for the reductive deiodonation of the compound (1-phenyl-2-amino-3-iodopropane), the reaction is carried out preferably at high temperature to produce the desired compound, 1-phenyl-2-aminopropane. Suitable reductive dehalogenating agents are Raney nickel and lithium aluminium hydride. Although Hydroiodic acid itself maybe effective as the reductive dehalogenating agent, in this case the reaction is too slow to be practical"

this is because from a mechanistic point of view the aziridine is formed and easily reduced temperatures that high in this type of reduction poses the problem of phosphine gas formation.
also those high temps tend to split aziridines into phenylacetones which undergo aldol condensations and make tar.
follow that example if you like tarry crap at the end of the rxn.
so i'm wondering how java's expiriments turned out to work and this patent says that the terminal iodoalkanes sluggishly reduce, i doubt the veracity of that patent.
this method would be interesting to apply to tryptophan amt seems interesting.

Have you noticed the similarity of 1-phenyl-2-amino-3-iodopropane and nitrgen mustard gas. They both contain N-CH2-CH2-X part (Cl in the mustard, Iodine here). The compound 1-phenyl-2-amino-3-iodopropane should be very toxic due to possible formation of Cyclo (-N-CH2-CH2-)(+)I(-) ring, which is the way mustard gas acts.

In brief - even traces of 1-phenyl-2-amino-3-iodopropane should be avoided at all cost in the final product!!!
Isn't there an alternative way of reducing the OH group? I may read some about it.

Reference Information



Determination of Organic Halogen with Sodium Biphenyl Reagent
L. M. Liggett
Anal. Chem.,1954, 26 (4), pp 748–750


Excerpt
In this investigation quantitative recovery of
halogen was obtained with all of these compounds using the
biphenyl reagent. No chloro or bromo compounds have been
found to date for which the reagent is ineffective. hpplication to
fluorine compounds iyas not investigated. The method is particularly
adapted to samples containing small amounts of halogen
as there is no limit on sample size, although it is equally satisfactory
with small samples having a higher halogen content. The
method is less suitable for samples containing large amounts of
substances with reactive hydrogen such as water, alcohol, etc.
The procedure is particularly suitable for routine work because
it is simple, rapid, and readily adaptable to multiple determinations.
A single determination can be made in 20 minutes once a
stock of reagent has been prepared. For routine work eight
samples per hour can be run. The method has been used in the
author’s research and control laboratories for the past 5 years.

Chloramphenicol can obviously be a precursor, but it is having nitro group in p-position making corresponding amphetamine inactive. I wonder if there are any antibiotics analogues of C. without nitro group..

this poster claimed complete success.  the poster first referenced the SM thread, and a WD thread, and after some discussion, posted his/her modified version.

? ? ?? . . ? ?? ??. ? ?? ? ?? .
? ?? LiBH4 ? ?? ? (3,96 ??) ?? (90??) ? 3,6 ??. LiAlH4, ?? ? (46 ??). ?? ? ?? 0 ?? ? ?? ?? (15??).
? ?? ?? ?? ?? ?? ??. ?? ? ?? ?? ? ?? 0 ?? ? ?? ? NaOH (120??) ? ?, 2.5??. NaOH ?? 20??.?? ? ?? ? ?, ?? 15??. , ? ? ? ? Na2SO4. ??
? ?? (0 ??) 8,76 ?? ? ? ?? (100??) ? 6,66 ?? ?,? 1,95 ?? . ?? ? ? ?? ?? ? ? 30 , ? ?? ?? ?? ? ? (170??) 14 ??. ?? ? ? ? ? ? ? ? 2 ??. ?? ?? ? ?? ? ? ? ?? ?? ??, ? (Na2SO4),? . ?? ?? ? ?, ? ?? ? ? ?? 13,8 ??. ? ??.



translation coming shortly

Delivered as promised.  Everything tested, including bioassay.  The phenylalanine was obtained from “Revord” brand pills.  To a cold LiBH4 water solution(3.96g), 90ml of THF was added. Along with 3.6g LiAlH4, followed by 46ml of trimethylsilyl chloride.
The mixture was cooled to 0° C and 15g of phenylalanine was added.  Once the reaction had calmed, it was removed from the cooling bath.  Then the mixture was again cooled down to 0° C, and 120ml of NaOH solution(2.5g/20ml H2O) was added in small increments.  The mixture was evaporated, and the phenylalaninol was recrystallized in 15ml of dichloromethane, and dried with Na2SO4.
Next, to a cooled(0° C) suspension of 8.76g Triphenylphosphine in 100ml of dry dichloromethane, 6.66g of iodine was added, along with 1.95g of Imidazole.  The mixture was brought to room temperature within 30 minutes, and then a solution of phenylalaninol in dichloromethane, 14g/170ml, was added in small portions.  The mixture was heated in water for 2 hours.  Once cooled, the mixture was filtered and made acidic with dilute sulfuric acid, dried with Na2SO4, and evaporated.  After cleaning through a short column, and recrystallization in ISO alcohol, 13.8g of amphetamine sulphate was obtained.

this was posted by sn: Dark Raziel
on a no longer existing Russian language forum.