A Study of Impurities Found in Methamphetamine Synthesized From Ephedrine
      A Study of Impurities Found in Methamphetamine Synthesized From Ephedrine
      by T.S. Cantrell et. al., Forensic Science international 39, 39-53 (1988) 
      Summary
      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.
      Introduction
      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 [1]. Finally, impurities in 
      methamphetamine are important to forensic chemists performing sample 
      analysis due to possible interferences with the analytical technique being 
      used.
      1. SOCl2
      I: (-)-Ephedrine =============> Methamphetamine
      2. H2/Pd
      HI/P
      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 [2]. 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.
      Chemistry
      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 [4]. 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 [5].
      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 [6]. 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.
      References
        Conference: "Toxic Effects of Impurities in Methamphetamine From 
        Clandestine Labs: Huntington's Chorea", San Francisco, July 15, 1986, 
        sponsored by U.S. Drug Enforcement Administration. For information on 
        previously identified impurities, consult the following: 
          T.C. Kram, J. Forensic Sci, 24 (1979) 596-599; 
          T.C. Kram, J. Forensic Sci, 22 (1977) 40-52; 
          F.T. Noggle, J. Assoc. off AnaL Chem., 68 (1985) 1213-1222. 
        A.C. Allen, Methamphetamine from Ephedrine I, Chloroephedrines and 
        aziridines. J. Forensic Sci., 32 (1987) 953-962. 
        K.N F. Shaw, J. Org. Chem., 21 (1956) 1149-1151 (Foot-note 36). 
        E. Ogata, Helv. Chem Acta, 12 (1929) 873-877. 
        Milos Hudlicky, Reductions in Organic Chemistry, Halsted Press, John 
        Wiley and Sons, 1984, p. 31. 
        T. Taguchi, Chem. Pharm. Bull. 7 103-107 (1959). 
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