1. Routes of synthesis
     Via substitution at the 2-ethyl position    ...  

2. References

3. [Potentially relevant background material to be integrated, esp. for reaction attributions]
     Illegal synthesis  

Syntheses of amphetamine and methamphetamine encompass a broad swath of organic chemistry, with more than seventy known chemical precursors. In some cases a wide variety of reagents have been applied to bring about the same reaction. Funded by pharmaceutical companies, government grants, and illegal chemists, the reactions have progressed in step with organic chemistry as a whole.^[1][2] Exploration of a broader range of designer drugs based on the phenethylamine skeleton led to the syntheses of potent amphetamine derivatives with very different psychoactive effects, such as MDMA ("Ecstasy") and trimethoxyamphetamine, a mescaline-like compound.^[3]

Routes of synthesis

The following reaction schemes are organized according to retrosynthetic analysis, i.e. the most immediate precursor is described, followed by an explanation of the reaction schemes used to produce it.

Via substitution at the 2-ethyl position

Many popular syntheses involve removing some functional group from the 2-ethyl position of precursor compounds which may be natural products or legally obtainable. Commonly this is a hydroxyl group, found in ephedrine and pseudoephedrine (which differ only in the orientation of the -OH).^[4][5] The (pseudo)ephedrine may in turn result from reduction of another compound, such as an oxime with a ketone at the 2-position.^[5]

The conceptually similar Emde route involves reduction of ephedrine to chloroephedrine using thionyl chloride (SOCl₂), followed by catalytic hydrogenation. The catalysts for this reaction are palladium or platinum.^[22][14] The Rosenmund route also uses hydrogen gas and a palladium catalyst poisoned with barium sulfate (Rosenmund reduction), but uses perchloric acid instead of thionyl chloride.^[15]

The Birch reduction, also called the "Nazi method", became popular in the mid-to-late 1990s and comprised the bulk of methamphetamine production in Michigan in 2002.^[7] It reacts pseudoephedrine with liquid anhydrous ammonia and an alkali metal such as sodium or lithium. The reaction is allowed to stand until the ammonia evaporates.^[16] However, the Birch reduction is dangerous because the alkali metal and ammonia are both extremely reactive, and the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added. It has been the most popular method in Midwestern states of the U. S. because of the ready availability of liquid ammonia fertilizer in farming regions.^[17][18]

In recent years, a simplified "Shake 'n Bake" one-pot synthesis has become more popular. The method is suitable for such small batches that pseudoephedrine restrictions are less effective, it uses chemicals that are easier to obtain (though no less dangerous than traditional methods), and it is so easy to carry out that some addicts have made the drug while driving.^[19] It involves placing crushed pseudoephedrine tablets into a nonpressurized container containing ammonium nitrate, water, and a hydrophobic solvent such as Coleman fuel^[20] or automotive starting fluid, to which lye and lithium (from lithium batteries) is added. Hydrogen chloride gas produced by a reaction of salt with sulfuric acid is then used to recover crystals for purification. The container needs to be "burped" periodically to prevent failure under accumulating pressure, as exposure of the lithium to the air can spark a flash fire.^[20] The battery lithium can react with water to shatter a container and potentially start a fire or explosion.^[20]

...

[1-phenylpropan-2-imine]

Achiral but reacts with Ir-(S,S)-f-binaphane and H2 to produce chiral dextroamphetamine

From 2-phenylacetonitrile via MeMgI^[21][22]

E-(2-nitroprop-1-enyl)benzene

Reacts with 1-phenylpropan-3-amine and SmI₂ to produce racemic amphetamine^[23][24]

[*** The following should be listed under the azide, once I confirm with the original reference]

S-1-phenylpropan-2-ol

This is reacted with sodium azide, followed by reduction with H2 on Pd/C catalyst.^[25][26]

From 2-benzyloxirane via LiAlH4, which is from (R)-3-phenylpropane-1,2-diol via TsCl and sodium hydride, which is from (R)-3-phenyl-2-(phenylaminooxy)propan-1-ol via Pd/C, which is produced from 3-phenylpropanal with nitrosobenzene, L-proline, and sodium borohydride.

References

[Potentially relevant background material to be integrated, esp. for reaction attributions]

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist, Lazăr Edeleanu, who named the drug phenylisopropylamine.^{[205][207][208][209]}

Methamphetamine constituted half of the amphetamine salts for the original formulation for the diet drug Obetrol.^[5]

In 1997 and 1998, researchers at Texas A&M University claimed to have found amphetamine and methamphetamine in the foliage of two Acacia species native to Texas, A. berlandieri and A. rigidula.^[212][213] Previously, both of these compounds had been thought to be purely synthetic.^{[212][213][233]} These findings have never been duplicated and consequently the validity of the report has come into question.^[214]

As early as 1919, Akira Ogata synthesized methamphetamine via reduction of ephedrine using red phosphorus and iodine. Later, the chemists Hauschild and Dobke from the German pharmaceutical company Temmler developed an easier method for converting ephedrine to methamphetamine. As a result, it was possible for Temmler to market it on a large scale as a nonprescription drug under the trade name Pervitin (methamphetamine hydrochloride). It was not until 1986 that Pervitin became a controlled substance, requiring a special prescription to obtain.^[215] Pervitin was commonly used by the German and Finnish militaries.^[216][217]

Illegal synthesis

Methamphetamine is most structurally similar to methcathinone and amphetamine. Synthesis is relatively simple, but entails risk with flammable and corrosive chemicals, particularly the solvents used in extraction and purification. The six major routes of production begin with either phenyl-2-propanone (P2P) or with one of the isomeric compounds pseudoephedrine and ephedrine.^[218]

One procedure uses the reductive amination of phenylacetone with methylamine,^[219] P2P was usually obtained from phenylacetic acid and acetic anhydride,^[220] and phenylacetic acid might arise from benzaldehyde, benzylcyanide, or benzylchloride.^[15] Methylamine is crucial to all such methods, and is produced from the model airplane fuel nitromethane, or formaldehyde and ammonium chloride, or methyl iodide with hexamine.^[221] This was once the preferred method of production by motorcycle gangs in California,^[222] until DEA restrictions on the chemicals made the process difficult. Pseudoephedrine, ephedrine, phenylacetone, and phenylacetic acid are currently DEA list I and acetic anhydride is list II on the DEA list of chemicals subject to regulation and control measures. This method can involve the use of mercuric chloride and leaves behind mercury and lead environmental wastes.^[17] The methamphetamine produced by this method is racemic, consisting partly of the less-desired levomethamphetamine isomer,^[223] though separation of the two enantiomeric forms through selective recrystallization of the tartrate salt can occur in order to isolate the more active dextromethamphetamine.^[224]

The alternative Leuckart route also relies on P2P to produce a racemic product, but proceeds via methylformamide in formic acid to an intermediate N-formyl-methamphetamine, which is then decarboxylated with hydrochloric acid.^[218][15]

Illicit methamphetamine is more commonly made by the reduction of ephedrine or pseudoephedrine, which produces the more active d-methamphetamine isomer. The maximum conversion rate for ephedrine and pseudoephedrine is 92%, although typically, illicit methamphetamine laboratories convert at a rate of 50% to 75%.^[225] Most methods of illicit production involve protonation of the hydroxyl group on the ephedrine or pseudoephedrine molecule.

Though dating back to the discovery of the drug, the Nagai route^[226] did not become popular among illicit manufacturers until ca. 1982, and comprised 20% of production in Michigan in 2002.^[7] It involves red phosphorus and hydrogen iodide (also known as hydroiodic acid or iohydroic acid). (The hydrogen iodide is replaced by iodine and water in the "Moscow route"^[8]) The hydrogen iodide is used to reduce either ephedrine or pseudoephedrine to methamphetamine.^[17] On heating the precursor is rapidly iodinated by the hydrogen iodide to form iodoephedrine. The phosphorus assists in the second step, by consuming iodine to form phosphorus triiodide (which decomposes in water to phosphorous acid, regenerating hydrogen iodide). Because hydrogen iodide exists in a chemical equilibrium with iodine and hydrogen, the phosphorus reaction shifts the balance toward hydrogen production when iodine is consumed (see Le Châtelier's principle).^[9] In Australia, criminal groups have been known to substitute "red" phosphorus with either hypophosphorous acid or phosphorous acid (the "Hypo route").^[8][10][11] This is a hazardous process for amateur chemists because phosphine gas, a side-product from in situ hydrogen iodide production,^[12] is extremely toxic to inhale. The reaction can also create toxic, flammable white phosphorus waste.^[17] Methamphetamine produced in this way is usually more than 95% pure.^[13]

The conceptually similar Emde route involves reduction of ephedrine to chloroephedrine using thionyl chloride (SOCl₂), followed by catalytic hydrogenation. The catalysts for this reaction are palladium or platinum.^[218][14] The Rosenmund route also uses hydrogen gas and a palladium catalyst poisoned with barium sulfate (Rosenmund reduction), but uses perchloric acid instead of thionyl chloride.^[15]

The Birch reduction, also called the "Nazi method", became popular in the mid-to-late 1990s and comprised the bulk of methamphetamine production in Michigan in 2002.^[7] It reacts pseudoephedrine with liquid anhydrous ammonia and an alkali metal such as sodium or lithium. The reaction is allowed to stand until the ammonia evaporates.^[16] However, the Birch reduction is dangerous because the alkali metal and ammonia are both extremely reactive, and the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added. It has been the most popular method in Midwestern states of the U. S. because of the ready availability of liquid ammonia fertilizer in farming regions.^[17][18]

In recent years, a simplified "Shake 'n Bake" one-pot synthesis has become more popular. The method is suitable for such small batches that pseudoephedrine restrictions are less effective, it uses chemicals that are easier to obtain (though no less dangerous than traditional methods), and it is so easy to carry out that some addicts have made the drug while driving.^[19] It involves placing crushed pseudoephedrine tablets into a nonpressurized container containing ammonium nitrate, water, and a hydrophobic solvent such as Coleman fuel^[20] or automotive starting fluid, to which lye and lithium (from lithium batteries) is added. Hydrogen chloride gas produced by a reaction of salt with sulfuric acid is then used to recover crystals for purification. The container needs to be "burped" periodically to prevent failure under accumulating pressure, as exposure of the lithium to the air can spark a flash fire.^[20] The battery lithium can react with water to shatter a container and potentially start a fire or explosion.^[20]

Rarely, the impure reaction mixture from the hydrogen iodide/red phosphorus route is used without further modification, usually by injection; it is called "ox blood".^[16] "Meth oil" refers to the crude methamphetamine base produced by several synthesis procedures. Ordinarily it is purified by exposure to hydrogen chloride, as a solution or as a bubbled gas, and extraction of the resulting salt occurs by precipitation and/or recrystallization with ether/acetone.^[16]

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