Enantiomers Separation. Method 1.1. R,R-Tartaric Acid

[GhostChemist]

Enantiomers Separation. Method 1.1. R,R-Tartaric Acid​

Literature Information​

Optical rotation at λ=589 nm of Na D-lines, cuvette 1 dm (100 mm)​

Substance​	Optical rotation [α]D20​	Concentration c (g/100 ml)​	Solvent​
D-(-)-Tartaric acid CAS 147-71-7​	-11.5 – (-13.5) -11 – (-13) -11.9 -12.2​	10 20 20 20​	H2O H2O H2O H2O​
L-(+)-Tartaric acid CAS 87-69-4​	+11.5 to +13.5 +13.0±1.0 +12.2​	10 20 20​	H2O H2O H2O​
S-(+)-Methamphetamine​	+14.0 - +20.0 +16 to +19 +17.9​	1 (FB) 2 (hydrochloride) 3 (hydrochloride)​	1М HCl H2O H2O​
R-(-)-Methamphetamine​	−14 – (-15) −24.7 −18.2 -17.4​	1 (FB) 5 (hydrochloride) 0.115 (hydrochloride) 3 (hydrochloride)​	1M HCl H2O H2O H2O​
L-Ephedrine​	-33 – (-33.5) -29.5 – (-32)​	5 (hydrochloride) 5 (sulphate)​	H2O H2O​
D-Pseudoephedrine​	+51 +62 +61 - +62.5​	0.6 (FB) 0.8 (hydrochloride) 5 (hydrochloride)​	EtOH EtOH H2O​
S-(+)-Amphetamine​	+24.2​	5 (hydrochloride)​	H2O​
R-(-)-Amphetamine​	-24.7​	5 (hydrochloride)​	H2O​
(R)-(-)-Methamphetamine (R,R)-tartrate​	+4.77​	5​	H2O​
(S)-(+)-Methamphetamine (R,R)-tartrate​	+22.1​	5​	H2O​

References​

1. Thermo Fisher Scientific Data https://www.thermofisher.com/order/catalog/product/137862500?SID=srch-srp-137862500​
2. Merck Index, 15th ed., O’Neil, M.J., Royal Society of Chemistry, Cambridge, UK, 2013​
3. European Pharmacopoeia, 10th ed., Monograph, 2019​
4. https://www.sigmaaldrich.com/BE/en/product/aldrich/t206?srsltid=AfmBOooB-rRbc_b1L49y4GZ-_5h0Nb6WspEmvodnRfiTXIrjsaqZRjv4
5. Dobšíková K.; Michal, P.; Spálovská, D.; Kuchař, M.; Paškanová, N.; Jurok, R.; Kapitán, J.; Setnička V. Conformational analysis of amphetamine and methamphetamine: a comprehensive approach by vibrational and chiroptical spectroscopy. Analyst 2023, 148, 1337–1348. https://pubs.rsc.org/en/content/articlelanding/2023/an/d2an02014a DOI https://doi.org/10.1039/D2AN02014A​
6. The Japanese Pharmacopoeia, 17th ed.; Ministry of Health, Labour and Welfare: Tokyo, Japan, 2016​
7. O'Neil M.J., Smith A., Heckelman P.E. The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. 1996​
8. European Pharmacopoeia v8.0 (2014)​
9. Elemer Fogassy, Maria Acs, Ferenc Faigl. Pseudosymmetry and Chiral Discrimination in Optical Resolution via Diastereoisomeric Salt Formation. The Crystal Structures of (R)- and (S)-N-Methylamphetamine Bitartrates (RMERTA and SMERTA). J. CHEM. SOC., PERKIN TRANS. II, pp. 1881-1886, 1986. doi:10.1039/P29860001881​

10. 537-46-2 CAS MSDS (D-METHAMPHETAMINE) Melting Point Boiling Point Density CAS Chemical Properties

    ChemicalBook Provide 537-46-2(D-METHAMPHETAMINE)Melting Point Boiling Point Density,537-46-2(D-METHAMPHETAMINE) CAS Chemical Properties MSDS.

    www.chemicalbook.com

11. (S)-(+)-Methamphetamine

    ChemSpider record containing structure, synonyms, properties, vendors and database links for (S)-(+)-Methamphetamine, 537-46-2, Metamfetamine, MYWUZJCMWCOHBA-VIFPVBQESA-N

    www.chemspider.com

Main Calculation Formulas​

​

Calculation of the standard rotation angle:​

Calculation of the observed angle of rotation:​

​

Were:

[α]D20 – angle of rotation at temperature 20℃ and at λ=589 nm of Na D-lines
[α] – observed rotation angle on a polarimeter
l – length of the cuvette, 20 мм = 0.2 дм
с – Concentration, g/100 ml

​

FB Obtaining​

The process of FB separation is shown in Scheme 1

Scheme 1​

Starting Reagents and Materials

• 120 g Methamphetamine hydrochloride
• 1300-1500 ml H2O
• 30 g NaOH
• 60 g NaCl
• 250-300 ml DCM
• 2 g molecular sieves 3A
• Separations funnel 2000 ml
• Beakers
• Funnel
• Paper filter
• Indicator strips рН 0-14

Synthesis

120 g of Methamphetamine hydrochloride is dissolved in 400-500 ml of water.​

Fig 1​

Stir until the Methamphetamine hydrochloride is completely dissolved.​

Fig 2​

A sodium hydroxide solution is prepared: 30 g NaOH in 200 ml water​

Fig 3​

The alkali solution is cooled to room temperature.​

Fig 4​

A solution of sodium chloride is prepared: 60 g and 200 ml of water.​

Fig 5​

The mixture is stirred until NaCl completely dissolved.

Fig 6​

The Methamphetamine hydrochloride solution is transferred into a separatory funnel

Fig 7​

A solution of Methamphetamine hydrochloride (especially after long-term storage) is purified with 4 portions of 50-70 ml of DCM.​

Fig 8​

The mixture is shaken well.​

Fig 9​

The mixtures are given time for the layers to separate. The DCM layer is discarded.​

Fig 10​

Purification is carried out until a colorless layer of DCM is obtained.​

Fig 11​

After purification of DCM, the Methamphetamine hydrochloride solution is filtered through a paper filter. The funnel and filter are rinsed with new portions of water.​

Fig 12​

Filtration of Methamphetamine hydrochloride solution​

Fig 13​

Filtered solution of Methamphetamine hydrochloride​

Fig 14​

The filtered solution of Methamphetamine hydrochloride is transferred to a clean separatory funnel.​

Fig 15​

A prepared solution of sodium hydroxide at a temperature not higher than room temperature is added to the solution of Methamphetamine hydrochloride.​

Fig 16​

For better separation of Methamphetamine FB, a sodium chloride solution is added.​

Fig 17​

The mixture is kept for 30-60 minutes.​

Fig 18​

The lower alkaline layer is separated and discarded or subjected to extraction.​

Fig 19​

The FB layer is kept for 20-30 minutes.​

Fig 20​

FB layer​

Fig 21​

The FB layer is drained into a sealed bottle for further storage.​

Fig 22​

2g of 3A molecular sieves are added to the FB​

Fig 23​

Separated FB and dried with 3A molecular sieves. FB weight 94.2 g (yield 97%)​

Fig 24​

EXPERIMENT 1​

Method 1.1. Resolution with Using R,R-Tartaric Acid​

​

The separation process proceeds according to Scheme 2

Scheme 2​

Starting Reagents and Materials​

• 10 g FB + 20 ml EtOH(abs)​
• 10 g L-(+)-Tartaric acid + 60 ml EtOH(abs) full dissolution by stirring on a magnetic stirrer​
• 3 days of stirring at 5-10℃​

Synthesis​

R,R-tartaric acid (L-(+)-Tartaric acid) CAS 87-69-4​

Fig 25​

R,R-tartaric acid (L-(+)-Tartaric acid) (10 g) was dissolved in absolute ethanol (60 ml)​

Fig 26​

Full dissolution is carried out by using a magnetic stirrer​

Fig 27​

10 g of Methamphetamine free base is collected and placed into a flask.​

Fig 28

Fig 29​

Racemic Methamphetamine free base (10 g) was dissolved in absolute ethanol (20 ml)​

Fig 30

Fig 31​

A solution of R,R-tartaric acid (L-(+)-Tartaric acid) is added to a solution of Methamphetamine FB in ethanol.​

Fig 32

Fig 33​

Then the RM is stirred for 72 hours at T = 5-10℃​

Fig 34​

After some time, a sediment precipitation in the RM​

Fig 35​

After 72 hours of stirring, the precipitate is filtered off using a porous filter.​

Fig 36​

The residue in the flask is washed off with a small portion of alcohol 15-20 ml​

Fig 37​

The filtered precipitate is dried directly in a vacuum and then for 48 hours in a desiccator over alkali.​

Fig 38

Fig 39​

The dried Methamphetamine tartrate (precipitate). Yield 11.82 g (59.1%)​

Fig 40​

The mother liquor is evaporated.​

Fig 41

Fig 42

Fig 43

Fig 44​

The mother liquor does not crystallize after evaporation. This can occur for several reasons: alcohol-soluble impurities (including resins) migrate into the mother liquor, as well as excess tartaric acid.​

Fig 45

Fig 46​

Since tartrate is very difficult to convert into dry residue, Methamphetamine tartrate was converted to Methamphetamine hydrochloride. 100-150 ml of 20% sodium hydroxide is prepared.​

Fig 47​

An alkali solution is added to the Methamphetamine tartrate syrup.​

Fig 48

Fig 49​

The resulting homogeneous RM is transferred to a separatory funnel.​

Fig 50​

Extraction of FB is carried out with 3-4 portions of DCM, 30-50 ml each.​

Fig 51

Fig 52​

The mixture is shaken well and left to stand to separate the layers.​

Fig 53​

The DСM layer is separated (total volume 150-200 ml).​

Fig 54​

Hydrochloric acid is added to the separated DCM layer and stirred for 20-30 minutes. The aqueous layer should have an acidic or slightly acidic pH.​

Fig 55​

The mixture is transferred to a separatory funnel. The DCM layer is separated and discarded.​

Fig 56​

The aqueous acidic layer is evaporated until crystallization occurs. It is dried in a desiccator over alkali under vacuum for 24-48 hours. It is washed with petroleum ether if further purification is necessary.​

Fig 57

Fig 58​

Methamphetamine hydrochloride. Yield 6.7 g (33.5%)​

Fig 59​

Determination of Optical Rotation of the Obtained Substances​

​

To determine the optical rotation, a polarimeter with a cuvette length of 20 mm was used.

For the separated M tartrate precipitate ((R)-(-)-N-methylamphetamine (R,R)-tartrate (RMERTA)), a standard solution of 0.5 g in 10 ml of water is prepared. A certified Class A volumetric flask is used.​

Fig 60​

The values of the observed rotation angle in 3 measurements on a polarimeter showed 0.12, which corresponds to the rotation angle [α]D20 = +12 (literature data is +4.77), which approximately corresponds to the optical enantiomer (R)-(-)-N-methylamphetamine (R,R)-tartrate​

Fig 61​

For the mother liquor, which was converted into M hydrochloride, a solution of 0.3 g in 10 ml of water was prepared.​

Fig 62​

The values of the observed rotation angle on the polarimeter showed 0.11 in 3 measurements, which corresponds to the rotation angle [α]D20=+18.3 (literature data is +17.9) and the optical enantiomer (S)-(+)-N-methylamphetamine hydrochloride.​

Fig 63​

Conclusions​

• The method allows to separate racemic Methamphetamine into levo- and dextro-Methamphetamine with a yield of 59.1% and 33.5%, respectively.​
• (R)-(-)-N-methylamphetamine (levo-) remains in the precipitate in the form of (R,R)-tartrate. (S)-(+)-N-methylamphetamine (dextro-) also remains in the mother liquor in the form of the more soluble (R,R)-tartrate. This creates further problems in separating the dextro-isomer, since impurities (pollutants, resins, etc.), as well as excess of (R,R)-tartaric acid, pass into the mother liquor.​
• According to obtained optical rotation values, it is show that the precipitated (R)-(-)-N-methylamphetamine (R,R)-tartrate contains a significant portion of (S)-(+)-N-methylamphetamine (R,R)-tartrate. Recrystallization is required for more complete separation.​
• Using the separated levo-M, it is possible to regenerate enantiomerically pure tartaric acid and use (R)-(-)-N-methylamphetamine FB for further separation of racemic tartaric acid and for generating a quantity of enantiomeric separation reagents.​

 

[Osmosis Vanderwaal]

Thanks for this. I have a question though. not really a question, but a couple of years ago we were discussing this in the G,Patton authored method posted on this site using D,L-tartaric acid, and the conversation went to the methamphetamine tartrate and I wondered why there was no L- meth D-tartrate or D-meth-L-tartrate listed in his reaction, and he linked me to a document that said that these non-optically active enantiomers were sterically hindered from forming. you disagree?a

 

[GhostChemist]

All materials are based exclusively on practical results and scientific data.
Having studied this issue on optical isomers, we came to the conclusion that the information (even in books from reputable publishers of recent years) very heavily distorted. Mistakes in scientific literature are common, especially in this theme about enantiomers.

We don't know whether these publication errors were made accidentally or intentionally, and we don't want to refut or discuss them.
We decided to conduct a series of isomer separation experiments and will publish the real results.

This is the first...

In the future, everything will become very clear and you will be able to get a real answer to your question based on practical data.

Follow the news!

 

[Osmosis Vanderwaal]

Do you speculate the existence or possible existence of R-methamphetamine-L-tartate? I sense that if it were a possibility, yields would be much lower using the methods people typically use. I haven't thought about it for even 1 minute yet, but it seems the stereoisomer techniques would be a total fail if both enantiomers were protonated

 

[Osmosis Vanderwaal]

R,S- methylampetamine-R,R-tartate has an optical rotation of 12. R,S-methylamphetamine-S,S-tartrate has an optical rotation of 12 Tartaric acid has an optical rotation of 12 ( aside from the mesomers which are not optically active. Something to consider when contemplating your unexpected 12° R-meth, R,R-tartrate that should have been 4.7. if it were truly R-meth R,R-tartrate, it should be more like 44° and R-meth, S,S-tartrate, if there is such and thing would be 20°?¿!¡

 

[GhostChemist]

What do you mean R,S-methylamphetamine-R,R-tartate? This compound can not be formed (only theoreticaly as tartrate because the tartaric acid is dibasic or diprotic acid). In this experiment we are used bitartrates.
Where did you get these numbers (44 and 20) of optical rotation for R-meth R,R-tartrate and R-meth-S,S-tartrate respectively from? Please link the scientific data.

See the table with optical rotation, all this information collect from scientific literature and confirm in our first experiment for (R)-(-)-Methamphetamine (R,R)-tartrate. Why rotation angle [α]D20 = +12 and why we can not obtained literature data of +4.77? Because (S)-(+)-Methamphetamine (R,R)-tartrate is present in the powder of (R)-(-)-Methamphetamine (R,R)-tartrate and it is increase the rotation angle to +12.​

 

[Osmosis Vanderwaal]

I mean a racemic mixture of meth reacted with 2R,3R-tartaric acid made in anticipation of steroisomer separation , the topic of this post, as far as I can tell. Your post definitely says methamphetamine multiple times. I previously asked your opinion on the paper I was linked that stated stearic hindrance prevented D-meth-L-tartrate from forming and you spoke of bad scientific data and not wanting to speculate. D-meth,L-tartrate is R-meth, R,R-tartrate (2R,3R-tartrate if you insist. I get these days from anywhere. Dozens of links, " optical rotation of 2R,3R-tartarc acid" You get an answer of something other than +12°? "R-methamphetamine optical rotation" is there something other to see besides +32°
32
+12___
44

R,S-methamphetamine optical rotation; 0
0
+12
12

S-methamphetamine optical rotation -17.8@25c anywhere you look
12
-17.8
-5.8°

If there's a value here you disagree with, which one? I just checked all of the figures again

 

[GhostChemist]

All this data of optical rotation obtain on scientific polarimeter. So, all conlusions acording optical rotation and, accordingly, the definition of the enantiomer are based solely on real data from device.

Will you dispute the data obtained by Japanese scientific polarimeter (calibrated and certified)?