Dextromethamphetamine fron Dextroamphetamine using Formic Acid and Formaldehyde is it possible or will it be racemic Methamphetamine.

[BlueDex]

I was wondering if Dextromethamphetamine could be made from Dextroamphetamine or if it would be racemic. The idea is to turn around 5% to 10% of the Dextroamphetamine into Dextromethamphetamine by adding 10% Formic acid slight excess maybe 11% and Formaldehyde 10% to Dextroamphetamine to get Dextromethamphetamine 10% and limit Dextrodimethamphetamine. Is it possible, or will it be racemic Methamphetamine and trace amounts of Dimethamphetamine

Making Dextromethamphetamine up to 8% to 10%.

Limit Dextrodimethamphetamine to maybe 1% or less.

An excess of Dextroamphetamine is used to limit the formation of Dextrodimethamphetamine.

So will it be Dextromethamphetamine, or Racemic Methamphetamine?!

 

[Doktor Faust]

The short answer is: under the reaction conditions, it is almost impossible to obtain any significant amount of methamphetamine, starting from amphetamine. The only product is N,N-dimethylamphetamine, together with the unreacted amphetamine.

The reaction in question is Eschweiler–Clarke procedure, i.e. exhaustive methylation of primary (and secondary) amines, using formaldehyde and formic acid. This is an old, but highly efficient method for the preparation of tertiary N,N-dimethyl-alkyl amines.

It is unlikely that any significant amount of a secondary amine (i.e. methamphetamine) will be obtained under the reaction conditions, regardless of the stoichiometry. Secondary amines are generally more reactive than primary ones, so they rapidly react further, yielding tertiary amines. In addition, the reaction requires elevated temperatures (~100oC), further reducing the selectivity, and the possibility of secondary amine formation.

In the case when a limited amounts of formic acid and formaldehyde are used (any amount lower then stoichiometric), the typical composition of the reaction mixture should be as shown below:

Thus, the desired product 3 (dextromethamphetamine or racemic methamphetamine) will be absent, almost certainly. (Any experimental analysis of the reaction mixture requires, at least, gas chromatography, preferably coupled gas chromatography-mass spectrometry).

Furthermore, even if some methamphetamine is produced, the mixture (1 + 2 +3) would be almost impossible to separate on a preparative scale (e.g. >1 g), due to similar boiling points and other characteristics (all three amines are fairly volatile, practically precluding column chromatography). The only choice would be preparative gas chromatography or preparative HPLC, both extremely expensive for the compounds in question. Thus, the whole experiment would be practically useless.


Mechanistically, the reaction involves the hydride transfer from formic acid, as shown bellow:

The question concerning the racemization is more complex, however it is relevant only to the tertiary amine 2. The possible racemization can occur, via the acid-catalyzed equilibrium of imines 1a and 1b, shown bellow. Also, transamination is possible, leading to ketone 4 and methylamine 5. All those reactions are a possibility only, not likely to proceed to any significant extent.

Thus, it is reasonable to expect N,N-dimethyl amine 2 in good yields as the only product, likely with little or no racemization.

Generally, the selective conversion of primary amines to the secondary ones (e.g. amphetamine to methamphetamine) requires different synthetic approaches. For example, reduction of secondary formamides with LiAlH4 or DIBAL-H, or alternatively, N-alkylation of amidate anions, derived from secondary carboxamides, such as formamides, or BOC carbonates, followed by acid hydrolysis. Some other methods exist as well.

Finally, methamphetamine (dextro or racemic) is not normally prepared from amphetamine on any significant scale, due to the relative complexity of the procedures and low cost-effectiveness. However, it is not impossible, albeit not using Eschweiler–Clarke procedure.​

 

[BlueDex]

So elevated temperatures means N,N-Dimethyldextroamphetamine 5% and leftover 95% Amphetamine. It was just to convert 10% of the Dextroamphetamine to Dextromethamphetamine. Maybe it would be better to use Formaldehyde to convert 10% of Dextroamphetamine using Palladium on Carbon and Aluminum Galinstan amalgam and only 1% of Formic acid under a Carbon Dioxide inert atmosphere. My idea is to only convert 10% of the Dextroamphetamine to Dextromethamphetamine. So maybe Formaldehyde 10% of it and Dextroamphetamine and Palladium on Carbon and Aluminum Galinstan amalgam and 1% of Formic Acid and a Carbon Dioxide inert atmosphere. Temperature 30°C and reaction time 24 hours and then maybe 5% to 10% will be Dextromethamphetamine. If Phenyl-2-Propanone and Methylamine can be used, then it can be racemic Methamphetamine. If Cyclohexyl-2-Propanone and Methylamine is used, Propylhexedrine will be obtained.

Monomethylation of Amphetamines - [www.rhodium.ws]

 

[Doktor Faust]

As explained previously, any variation of the formaldehyde approach to convert dextroamphetamime to dextromethamphetamine has no practical value, although insignificant amounts might be obtained. This is true regardless of the types of the reagents/reactants used, or their relative ratio. The conclusion definitively emerges from the large body of the published literature (papers, patents etc.), as well as from the actual experiments on various primary amines, other then the amphetamine itself. However, it cannot be ruled out that some researches attempted the reaction and published the results somewhere.

Also explained previously, the practical separation of any mixture, containing amphetamine, methamphetamine and N,N-dimethyl amphetamine is very difficult. The use of preparative gas chromatography or preparative HPLC probably would be effective, but highly impractical and expensive. Standard fractional distillation, under the reduced pressure, cannot separate the mixture, because the boiling points of the three amines are very close ( all three have b.p. in the range ~200-210oC/760 mmHg, or ~90oC/15 mmHg). In principle, it is possible to achive the separation using fractional distillation with spinning-band fractional column, Fig. 1, although the equppment is very expensive (see for example https://brinstrument.com/fractional-distillation/spinning-band-distillation).

Fig. 1​

Also mentioned previously, there are the alternative methods to convert dextroamphetamine 1 into dextromethamphetamine 3. Two of them are shown here in some detail.

Note. The specific transformations shown in Scheme 1 and 2 have not been performed experimentally, and are only expected to proceed by the analogy to the numerous similar reactions, which were actually performed. Thus, although it is very likely, there is no guarantee that the yields and the required conditions will be as shown. In practice, it means that anyone performing the synthesis will need to do some experiments, adjusting the reaction conditions and making variations of temperatures, reaction times, relative amounts of the reactants and reagents etc.

Good theoretical knowledge in organic chemistry as well as the proficiency in experimental organic synthesis is mandatory. Also, a solidly equipped lab.

METHOD 1.

Conversion of dextroamphetamine 1 into formamide 2, followed by the reduction of the formamide carbonyl group to methyl group. The product is dextromethamphetamine 3, Scheme 1
Most primary amines (if they are not sterically hindered) react directly with ethyl formate, resulting in the corresponding formamide. (Mechanistically, the reaction is aminolysis). In general, carbonyl group of carboxamides, including formamides, can be reduced to the methylene group, using various reducing agents. Those include LiAlH4 (lithium aluminium hydride), DIBAL-H (di-isobutyl aluminium hydride), various boranes (e.g. BH3) etc.
A simple and easy-to-use reducing reagent consists of a mixture of sodium borohydride (NaBH4) and elemental iodine (I2), in tetahydrofuran (THF). It was first described in a paper published in 1992 and extensively used ever since. (https://doi.org/10.1016/S0040-4020(01)81236-9). (The experimental details are given in the original paper, which can be downloaded, using DOI No 10.1016/S0040-4020(01)81236-9 from the address https://sci-hub.se/ It is also found in many later papers.

Scheme 1

The alternative reagents for the reduction are LiAlH4 and DIBAL-H, mentioned above. While very effective, they are more difficult to handle, pyrophoric and can explode in contact with water, alcohols etc. (Both are widely available commercially, the latter mainly in the solution).



METHOD 2, Scheme 2.

Formation, alkylation and cleavage of BOC derivative (carbamate) of dextroamphetamine 1

Primary amines react easily with many acylating agents (e.g. carboxylic acid chlorides, anhydrides etc.) providing the corresponding carboxamides. When a standard reagent known as BOC anhydride is used, the product is a BOC carbamate. In the case of dextroamphetamine 1, the structure of the resulting carbamate is 4, Scheme 2. The reaction of introducing BOC group, normally proceeds smoothly, in near quantitative yields. Carbamates like 4, possess a mildly acidic hydrogen, shown in magenta, which can be removed by strong bases, typically sodium hydride, NaH. It results in the formation of a salt 4a, where the anion is a moderately strong nucleophile and can be N-alkylated with various halogen alkanes, in this case methyl iodide. The N-methylated carbamate 5 should be obtained in good yields. The final step represents the cleavage of BOC group, which is an acid-catalyzed reaction. It proceeds easily and provides the free amino group, in the form of the salt. (This general reaction is well known from the peptide chemistry).

There is a number of literature reports that the deprotonation and alkylation step can be effected using aqueous NaOH instead of NaH in anhydrous solvent (DMF). These reactions proceed under phase-transfer conditions (PTC), i.e. in the presence of quaternary ammonium salts, such as TEBA or TBAB, Scheme 2B. The quaternary salts are often used in stoichiometric amounts, although the catalytic variants are also common. The second phase in the reaction is an organic solvent immiscible with water, usually toluene. Generally, PTC reaction are less likely to secure good yields in the reactions of this type (if any, since they may fail completely). Also, more side products are often encountered. Nevertheless, they are worth trying.​

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