Dextroamphetamine synthesis (Nabenhower, 1942)

[ASheSChem]

hooo yes ok , thanks
possible to save the L-amph part?

 

[dark_side_of_chemistry]

I read the original patent. there they wrote that per 2mol of amphetamine they add 1mol of tartaric acid and dissolve it in the right amount of alcohol. heat to a boil and set aside to crystallize. they separate the aqueous phase from the crystals and carry out another recrystallization. they repeat this operation several times. then alkali is added to the combined water phases to raise the pH to 11. two phases are formed. one is oil. I understood the original patent well. will the actions carried out in this way give the appropriate effect?https://patents.google.com/patent/US2276508A/en
Two mols, for example, 2'70 grams, of racemic e-methylphenethylamine base are reacted with one mol (1'50 grams) of d-tartaric acid, thereby forming d1-a-methylphenethylamine d-tartrate. a neutral salt. The neutral salt thus obtained is fully dissolved by the addition of sufficient, say about one liter, of absolute ethanol, and heating to about the boiling point. The solution is then allowed towel to room temperature with occasional stirring to eiiect crystallization. The crystals are filtered oil and will be found to contain a preponderance of the laevo enantiomorph. On recrystallization the preponderance of the lenantiomorph is increased and the process is repeated until no further change in optical rotation is effected and a reading of is obtained in a concentration of 8 grams per 100 cc. of aqueous solution. The product thus obtained is Liz-methylphenethylamine d-tartrate. The residual solid in the mother liquors is repeatedly and systematically crystallized, yielding a further fraction of biz-methylphenethylamine d-tartrate which may be purified by recrystallization. d-a-methylphenethylamine may be readily recovered from the mother liquors by the addition of tartaric acid thereto for the formation of acid tartrates and separation of d-a-methylphenethylamine d-bitartrate by crystallization.
The free base'of either optical isomer may be obtained by addition to the d-tartrate in the case of the laevo isomer and the d-bitartrate in the case of the dextro isomer of alkali in excess, as, for example, by the addition of an aqueous solution of caustic soda, which will cause the base to separate as an oil which may be recovered and purified by any well known procedure.

 

[diogenes]

Hi, I need some help! I have tried the Rusznak method for resolving racemic amphetamine. Here is the only information from Erowid, I tried to search for the paper, but could not find anything:

A mixture of 0.1 mole (13.52 g.) phenylisopropylamine (or 14.92 g. methamphetamine base) in 60 ml benzene, 0.05 mole d-tartaric acid (7.50 g.) in 30 ml water, and 2 g sodium hydroxide (reagent grade or titrated equivalent) in 3 ml water was kept 4 hours with intermittent shaking, and the organic phase evaporated to give 98% L-phenylisopropylamine. The aqueous phase was extracted with benzene at pH 13 and evaporated to give 96% D-enantiomer.​

I used half amounts compared to the description. Everything went fine, I got the Amphetamine disolved then base extracted with 30ml of Toluene (I didn`t have benzene - could this be the problem?), then added the other ingredients and kept for about 4 hours. There was some precipitate forming, but nothing some shaking in the separatory funnel would not help. Aqueous phase separated, and alkali given to PH 13. A nice layer of base formed on top of the water, so at this point I thought everything is fine. The base was extracted with 30ml of Toluene, however, when the acetone-sulphuric acid was added there was only a moderate precipitation, which did not increase, rather it started to disappear when a small layer of sulphuric acid - water was formed at the bottom of the beaker.

How can I save the hopefully D-Amphetamine extracted? I have also saved all the phases, so if someone points out a blunder earlier on, I can reverse. This is a very nice and easy method and I think it went fine, I just probably made some horrible mistakes in the simple extraction at the end. Actually wanted to re-read Patton`s extraction topic before starting with the final extraction, but was too excited and just went for it.
Any herlp would be appreciated.

My tips are:
- my acetone was not anhydrous - I distilled the acetone on NaSO4 yesterday and it was kept in a closed flask, but not in the freezer
- sulphuric acid contained water (it is pretty concentrated but not sure exactly - between 90-95%)
- I should have dried the Toluene before adding the acid - or perhaps just evaporate it a bit?
- Toluene is not the right solvent for this extraction for some reason (unknown to me).
- Should I reverse buy adding some alkali, then drying the Toluene, then let it evaporate?

 

[diogenes]

I have just realized that I omitted the last instruction which may be the solution to the problem.

The aqueous phase was extracted with benzene at pH 13 and evaporated to give 96% D-enantiomer.​

Still, even if evaporation works, what is the next thing to do to obtain D-Amphetamine sulphate? Just simply precipitate (acetone - sulphuric acid) but after evaporation? Why does it need to be evaporated? Is the reason that Toluene does not mix with Sulphuric acid, unlike IPA?

 

[G.Patton]

possible to save the L-amph part?

ASheSChemYes, you can filter L-amph D-tartaric acid after precipitation. Why are you reinventing the wheel? The method in this topic.

 

[ASheSChem]

sorry ;maybe i read too much for my little brain
you clearly explain it in the method..

Thanks for your works !

 

[diogenes]

Hi Patton, when you used 6g of the Amphetamine sulphate in the above extraction and then added half of the amount of D-Tartaric acid (in terms of mol). I think 3.3g is too much because when calculating the molar amount the freebase needs to be taken into account. 6g of Amphetamine sulphate is 4.4g freebase, which is 0.0326 Mol of base (1 Mol is 135g). We need 0.0326/2 Mol D-Tartaric acid which is roughly 2.446g. Let me know if my thinking is on the right track. If yes, then it is thanks to you for your Amphetamine salt topic. I was trying this extraction and tried to calculate how much L-Amphetamine-D-Tartaric acid precipitate I should get.

By the way first I got way too little precipitate, just above 1g after drying. I guess this is why the author of the patent says to continue the crystalisation until we get a solution with the right rotation? I`m thinking of trying to put the solution into the freezer so that more L-Amphetamine-D-Tartaric acid can precipitate? It would be much more comfortable not having to do the crystallisation so many times.

 

[G.Patton]

Hi Patton, when you used 6g of the Amphetamine sulphate in the above extraction and then added half of the amount of D-Tartaric acid (in terms of mol). I think 3.3g is too much because when calculating the molar amount the freebase needs to be taken into account. 6g of Amphetamine sulphate is 4.4g freebase, which is 0.0326 Mol of base (1 Mol is 135g). We need 0.0326/2 Mol D-Tartaric acid which is roughly 2.446g. Let me know if my thinking is on the right track. If yes, then it is thanks to you for your Amphetamine salt topic. I was trying this extraction and tried to calculate how much L-Amphetamine-D-Tartaric acid precipitate I should get.

diogenesYou absolutely right. I'll fix my mistake.

By the way first I got way too little precipitate, just above 1g after drying. I guess this is why the author of the patent says to continue the crystalisation until we get a solution with the right rotation? I`m thinking of trying to put the solution into the freezer so that more L-Amphetamine-D-Tartaric acid can precipitate? It would be much more comfortable not having to do the crystallisation so many times.

Let us know your result, please.

 

[Heartburn]

I've got two questions.
What to do with L-amph tartrate, since it's main effects are not very desirable for user?
What is the maximum shelf time of tartrate salts in comparison with sulphate/phosphate?

 

[G.Patton]

What to do with L-amph tartrate, since it's main effects are not very desirable for user?

HeartburnEffects weaker than d-amph sulphate.

What is the maximum shelf time of tartrate salts in comparison with sulphate/phosphate?

I can't say exactly, I think the same.

 

[diogenes]

I've got two questions.
What to do with L-amph tartrate, since it's main effects are not very desirable for user?
What is the maximum shelf time of tartrate salts in comparison with sulphate/phosphate?

HeartburnI would simply discard of L-amphetamine tartarate otherwise what is the point of separation?
I think tartarate salts are rather hydrophilic, they absorb water so storing them becomes more problematic, just like Amphetamine-HCL. This is why sulphate/phosphate salts are more desirable.

 

[Joker_55555]

Introduction​

At the moment, there are many ways to synthesize dextroamphetamine. They can be divided into 3 types: biosynthesis (using biomass), direct synthesis, and synthesis of racemic (the sum of l- and d-isomers) amphetamine followed by separation of optical isomers. In our case, a synthesis was chosen, in which simple reagents and rapid synthesis were used, which is maximally adapted to «home conditions». The process is as follows: we obtain the racemic amphetamine in the classical way, then we divide it into 2 optical isomers (l- and d-) by the Nabenhower method [US patent 2276508, Nabenhauer FP, "Method for the separation of optically active alpha-methylphenethylamine", published 17 March 1942, assigned to Smith Kline French].​

Synthesis​

Synthesis of amphetamine from P2NP via Al/Hg. First, we make an aluminum amalgam. It is needed in order to clean the aluminum from the strong oxide layer that forms when interacting with air. We take 14 g of aluminum foil and tear it with our hands into pieces of 2x2, 3x3 cm in size. Be sure to tear, not cut, to increase the surface area. Place into a 3-necked round-bottomed flask and fill the foil completely with water.​

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Now we are preparing the mercury salt. We take a mercury thermometer from the pharmacy, wrap it in paper, break it at the bottom tip. Pour all the mercury into a glass, where then add 4 ml of nitric acid (70%). Do not forget that mercury vapors are hazardous to health! To initiate the reaction, the glass had to be heated to about 50 degrees, stirring occasionally. All the mercury dissolved about for 30 minutes, and an orange gas, nitrogen oxide (IV), was released from the glass. The reaction equation is as follows:​

Hg + 4HNO3 ----> Hg(NO3)2 + 2NO2 + 2H2O

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Pipette 2 ml of the solution and place it in a round-bottom flask with foil. After about 5 minutes, the foil lost its shine, became dull, and a small layer of gray sludge (aluminum hydroxide) collected at the bottom of the flask.​

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We drain the liquid and rinse the foil with water 3 times.

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Pour 30 ml of water into the flask, insert a thermometer into the left throat of the flask, insert a reflux condenser into the central throat, and insert a dropping funnel with 110 ml of 14% P2NP (it is phenylnitropropene; 1-phenyl-2-methyl-2-nitroethylene) solution into the right throat.​

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Acetic essence is often used to produce hydrogen, but I "start" the reaction to produce hydrogen with water. Less acidic medium, which means less alkali must be added later. Many people ask the question: "How to remove this water?" There is no need to remove water anywhere, it reacts with aluminum and hydrogen is obtained:​

2Al + 6H2O ---> 2Al (OH) 3 + 3H2​

It is very important to remember that the reaction of P2NP reduction comes with a very! large exotherm. It is necessary to carefully monitor the temperature and prevent overheating above 60 degrees. Personally, I kept the temperature around 50-55 degrees. Failure to comply with this technology reduces the yield of the product and gives a colored (pink, orange) product. The infusion of the entire P2NP took about 50 minutes. Change the dropping funnel to a glass stopper. We got just such a gray solution.​

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To increase the yield, you can heat the reaction mass at a temperature of 50-60 degrees for 30 minutes in a water bath.

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We cool the mixture to room temperature, put a plug instead of the thermometer, remove the reflux condenser. We make an alkali solution based on 1 part of sodium hydroxide - 2 parts of water. Dissolution proceeds with heating, so we wait until the solution cools down. It is not worth pouring solid alkali into the reaction mass or pouring a hot solution, as this reduces the yield, like any overheating. Pour alkali cooled to room temperature to the reaction mass until pH = 11-12, wait 30-40 minutes until all the floating aluminum dissolves, yellow oil floats up. At the same time, we also monitor the temperature. Reaction equations:​

6NaOH + 2Al + 6H2O ---> 2Na3 [Al (OH) 6] + 3H2
3NaOH + Al (OH) 3 ---> Na3 [Al (OH) 6]

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We pour everything into a separating funnel. We are waiting for the separation of layers. Take the oily fraction.

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We extract amphetamine from the sludge, washing it 3 times with 10 ml of petroleum ether. Divide the upper part with a separating funnel. Combine all extracts with "oil" and put them in ice water for cooling.

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A large drop of water remains in the bottom of the glass, which is separated on a separating funnel. Pour the top layer into a glass and dry over anhydrous magnesium sulfate. There we clean the amphetamine from the remnants of mercury and water.​

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We filter the liquid from solid magnesium sulfate on a Buchner funnel.

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I take concentrated 98% sulfuric acid. Prepare a solution of sulfuric acid in acetone in a volume ratio of 1:10. I took the technical acetone, in the hardware store, and distilled it, taking away the "heads" and "tails". Then I dried it with anhydrous magnesium sulfate. Many people ask whether it is possible to make a solution in IPA. Yes, you can, but IPA (isopropyl alcohol) dries longer than acetone.​

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Drop by drop, carefully and with stirring, acidify with sulfuric acid in acetone to pH = 6. A white precipitate forms at the bottom.

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Cool the reaction mass in ice water, filter the precipitate on a Buchner funnel, rinse with 3 ml of cold acetone.​

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Air dry the filtered product and weight.

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7.55 g (0.0205 mol) of amphetamine sulfate was obtained.
Calculations:
m (P2NP) = 110 * 0.14 = 15.4 g.
n (P2NP) = 15.4 / 163.17 = 0.094 mol.
n (amphetamine sulfate) = n (P2NP) = 0.094 mol.
n (amphetamine base)= 0.0205 * 2 = 0.0410 mol.
The reaction yield is 0.0410 /0.094 = 43.6 %.
You will carry out different reaction with sulfuric acid. Amphetamine free base 2 mole + 1 mole of sulfuric acid = 1 mole of amphetamine sulphate. When you count amph. sulphate, you have to multiply by two your mole result of amph. sulphate cuz you take 2 mole amph. base for one mole of amph sulfate.​

Extraction of d-amphetamine​

We've got racemic amphetamine. It contains 1 molecule of d-amphetamine per 1 molecule of l-amphetamine. Next, we take 6 g of racemate and dissolve in 6 ml of water, add an alkali solution to pH = 11.​

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Extract with 5 ml of petroleum ether and warm the solution, add 2.45 g of d-tartaric acid in alcohol solution to the mixture. Then add alcohol until completely dissolved and cool with stirring. The l-amphetamine d-tartaric salt precipitates. The d-amphetamine remains in the solution. You can repeat procedure of cleaning precipitate of l-amphetamine d-tartaric salt by methanol to increase yield.​

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We precipitate d-amphetamine with an additional amount of d-tartaric acid. We filter the precipitate, get the base of d-amphetamine, adding alkali to pH = 11.

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We acidify the d-amphetamine base to pH = 6 with a solution of sulfuric acid in acetone. This gives 2.63 g of d-amphetamine sulfate. Yield 2.63 / 3 = 87.7%

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This extraction method valid to amphetamine, which was synthesized by any routes. There is another way to obtain dextroamphetamine.

G.PattonHi Can mercury chloride be used instead of mercury nitrate?

 

[Saul]

Hi Can mercury chloride be used instead of mercury nitrate?

Joker_333
yes

 

[UWe9o12jkied91d]

Hi Can mercury chloride be used instead of mercury nitrate?

Joker_333(II), (I) will not work

 

[SpeeD]

P2NP 14% in Nitroethane, correct? ​

G.Patton​

 

[UWe9o12jkied91d]

It's in isopropanol using nitroethane here as a solvent would be 1 stupid 2 wasteful

 

[G.Patton]

in Nitroethane

SpeeDIn IPA

 

[UWe9o12jkied91d]

I would simply discard of L-amphetamine tartarate otherwise what is the point of separation?
I think tartarate salts are rather hydrophilic, they absorb water so storing them becomes more problematic, just like Amphetamine-HCL. This is why sulphate/phosphate salts are more desirable.

diogenesYou can racemize the 50% lisomer you are left with and repeat as many times as possible.You do 3 of them bam 90% ish theoretical yield of the wanted isomer.

 

[diogenes]

You can racemize the 50% lisomer you are left with and repeat as many times as possible.You do 3 of them bam 90% ish theoretical yield of the wanted isomer.

UWe9o12jkied91dHow do you racemize it? I haven`t heard about such method.

 

[UWe9o12jkied91d]

How do you racemize it? I haven`t heard about such method.

diogenesHere you go, good sir, from the horse's mouth.Kind of dangerous to have the stuff laying around, so probably not worth it for the chemist producing for himself.This article talks about methyl-amp. but I am 100% sure you can do this with the unmethylated variant.

https://www.emcdda.europa.eu/publications/eu-drug-markets/methamphetamine/main-production-methods-europe_en#figure7

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