A Study of Impurities Found in Methamphetamine Synthesized From Ephedrineby T.S. Cantrell et. al., Forensic Science international 39, 39-53 (1988)
The synthesis of methamphetamine from ephedrine via reduction with hydriodic acid is discussed. Impurities which arise from this method are identified and rationalized. The in situ formation of iodoephedrine from ephedrine leads to trace impurities via internal substitution to 1,2-dimethyl-phenyl-aziridine, followed by retro ring-opening and hydrolysis to phenyl-2-propanone (P2P). This ketone or the retro ring-opened aziridine further condenses in an aldol condensation followed by dehydration to give 1-benzyl-methylnaphthalene and 1,3-dimethyl-2-phenylnaphthalene.
One of the most frequently abused drugs in the United States is methamphetamine, a stimulant popularly known as "crank" or "speed". That used in the illicit trade is synthesized in clandestine laboratories by a variety of routes and often contains impurities arising from incomplete reaction and inadequate purification of intermediates and/or the final product. Knowledge of these impurities is important for several reasons. It can provide useful intelligence concerning illicit production revealing information on the synthetic methods used to produce the drug, including necessary chemicals and equipment. Hence law enforcement officials can monitor the production and sale of commercially available precursors for methamphetamine and this can lead to the detection of clandestine laboratories. Secondly, interest in the presence or absence of specific impurities may lead to the identification of samples which are of a common origin, i.e. conspiracy links. A third area of interest in these impurities is in the potential harmful effects on methamphetamine users i.e. recent (1984-1986) developments indicate that possible methamphetamine impurities are responsible for cases involving Huntington's Choreform movement . Finally, impurities in methamphetamine are important to forensic chemists performing sample analysis due to possible interferences with the analytical technique being used.
I: (-)-Ephedrine =============> Methamphetamine
II: (-)-Ephedrine ==========> Methamphetamine
Fig. 1. Clandestine synthetic routes for (+)methamphetamine via (-)ephedrine. Route I employs a two step reaction process, thionyl chloride (SOCl2) followed by catalytic hydrogenation. Route II employs a one pot reaction with hydriodic acid and red phosphorus.
Allen and Kiser considered the stereochemistry, mechanism and by-products which result from the conversion of ephedrine to methamphetamine . In that process, ephedrine is converted to its chloro analog followed by catalytic reduction to methamphetamine, Fig. 1 (route I). In the present article, we discuss the conversion of ephedrine to methamphetamine via hydriodic acid reduction (route II). The chemistry involved in route II was advanced by information gathered from Allen and Kiser's article.
Illustration of the commonality of these syntheses is seen in the following facts. Stereochemistry implicit in the first route I also applies with hydriodic acid/red phosphorus reduction. That is, only (-)ephedrine and (+)pseudoephedrine yield (+)methamphetamine. Furthermore, the intermediate in route I (chloroephedrine from ephedrine with thionyl chloride) is a halo analog, and such is the case in route II. Ephedrine reacted with HI initially creates iodoephedrine in situ. Finally, the by-products of aziridines are common to both synthetic routes. Interestingly, there are significant mechanistic and by-product differences between these two routes, primarily due to the heated protic acid medium of the latter (route II) versus the ambient aprotic medium of the former (route I) which make further rearrangements in route II unique.
When ephedrine is heated with hydriodic acid, with red phosphorus (Caution!, Ref. 3) or without, initially the hydroxyl is replaced with iodine (to give iodoephedrine). It is from this point that the rearrangement chemistry of trace impurities starts. The halo compound is subject to reduction in the hydriodic acid medium leading to the target compound, (+)methamphetamine . Hydrogen iodide dissociates at higher temperatures to iodine and hydrogen, which effects hydrogenations. The reaction is reversible. Its equilibrium is shifted in favor of the decomposition by the reaction of hydrogen with organic compounds (iodoephedrine in this case) in the reduction, but it can also be affected by removal of iodine. This can be accomplished by allowing iodine to react with phosphorus to form phosphorus triiodide which decomposes in the presence of water to phosphorous acid and hydrogen iodide. In this way, by adding phosphorus to the reaction mixture, hydrogen iodide is recycled and the reducing efficiency of hydriodic acid is enhanced .
The halo compound may undergo an internal substitution reaction, whereby nitrogen replaces iodine to give an aziridine, which can decompose to give the compounds A (N-methylbenzylamine), B (benzaldehyde), C (propiophenone) and D (phenyl-2-propanone). Due to the extreme acidity of the reaction mixture, only routes C and D are viable considerations. The protonated nitrogen of the aziridine controls retro ring-opening to produce an zwitterion intermediate. The rational choice of route D, based on the highly favored zwitterion intermediate with resonance overlap to the aromatic ring, is borne out with experimental fact. The product of retro ring-opening, followed by hydrolysis of 1,2-dimethyl- phenyl-aziridine is P-2-P . Thus, P-2-P is a common impurity in these clandestine laboratory preparations of (+)methamphetamine. This anomaly has puzzled a number of forensic investigators where the clandestine synthesis was known to start from ephedrine and not the popular route P-2-P/methylamine Schiff base reduction via aluminium foil.
From the selected number of clandestine methamphetamine samples screened for the presence of trace impurities, we have found that the major portion of P-2-P produced in this reaction undergoes self-condensation (aldol) to afford hydrocarbon impurities. These impurities are 1-benzyl-3-methyl-naphthalene (E) and 1,3-dimethyl-2-phenylnaphthalene (F). Both compounds incorporate two molecules of P-2-P as result of an aldol condensation, followed by dehydration, followed by a second internal condensation and dehydration.