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Methamphetamine Synthesis Via HI/Red Phosphorous Reduction of Ephedrine
Harry F. Skinner
Forensic Science International, 48 128-134 (1990)
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Summary

The illicit manufacture of methamphetamine from ephedrine via reduction
with hydriodic acid and rod phosphorus is discussed. The stereochemistry.
mechanism, synthetic impurities, and analysis of clandestine
methamphetamine samples are addressed.

Introduction

The most common method of manufacture of methamphetamine in the United
States is the reduction of ephedrine with hydriodic acid and red phosphorus
(HI/red P) [1]. Manufacture of methamphetamine from phenyl-2-propanone
(P2P) and methylamine yields (+,-)methamphetamine, whereas the reduction of
(-)ephedrine or (+)pseudoephedrine yields (+)methamphetamine.

Even though the HI/red P ephedrine reduction method is relatively new
(1982) in clandestine laboratories, the method has been known for many
years and has been used to reduce carbonyl groups, nitrites, halides, and
alcohols [2,3]. Reduction of ephedrine to methamphetamine is well
documented in the literature. The configurations of ephedrine were
determined by reduction of the chloro- and bromoephedrines by Emde [4] and
Schmidt [5] using various reduction methods not including the Hl/red P
method. Emde incorrectly cites Ogata [6] as producing (+)methamphetamine in
1919 by heating (-)ephedrine or (+)pseudoephedrine with HI and yellow
phosphorus. The clandestine manufacture of (+)methamphetamine from
(-)ephedrine or (+)pseudoephedrine is a very simple process. A mixture of
ephedrine, red phosphorus, and hydriodic acid is heated, filtered, made
basic, extracted, and crystallized as the hydrochloride salt from
ether/acetone with hydrochloric acid or hydrogen chloride gas or from
trichloromonofluoromethane (i.e. "Freon 11') and hydrogen chloride gas. The
salt is filtered and dried. The theoretical yield is 92% by weight of the
precursor ephedrine, whereas the clandestine yields range from 50 to 75% by
weight of the precursor ephedrine. The final product varies from white to
orange/brown in color. It is usually greater than 95% in purity and
contains no ephedrine.


Results and Discussion

The HI/red P reduction of ephedrine to methamphetamine involves a cyclic
oxidation of the iodide anion to iodine and reduction of iodine back to the
anion by the red phosphorus, the latter being converted to phosphorous or
phosphoric acids [7,8].

The stereospecificity of the reduction results from mechanistic factors as
well as the diastereoisomeric nature of the ephedrines. Ephedrine and
pseudoephedrine are 1-phenyl-1-hydroxy-2-methylamino-propane; each contains
two chiral centers at the No. 1 and No. 2 carbons of the propane chain.
Reduction to methamphetamine eliminates the chiral center at the No. 1
carbon.

The diastereoisomers, (-)ephedrine and (+)pseudoephedrine, are reduced to
(+)methamphetamine, whereas the enantiomers reduce to (-)methamphetamine.
The (+,-) mixture of either ephedrine reduces to racemic methamphetamine.
The enantiomer and diastereoisomer of ephedrine selected as the precursor
dictates what isomer of methamphetamine will be produced.

The interesting aspect of the HI/red P ephedrine reduction is that P2P is
produced as an impurity in the synthesis. Normally, discovery of P2P in a
clandestine laboratory indicates that (+,-)methamphetamine, is the product.
However, the P2P is formed as an impurity and has no bearing on the
enantiomeric form of the synthesized methamphetamine, since the enantiomer
of the methamphetamine product depends solely on the enantiomer of the
ephedrine precursor.

The reaction mechanism for the reduction of ephedrine with Hl/red P is
summarized as follows. Ephedrine reacts with HI to form iodoephedrine
(iodomethamphetamine) which is predominately reduced to methamphetamine.
Iodoephedrine can undergo a ring closure to form 'aziridines'. The
'aziridines' (cis and trans-1,2-dimethyl-3-phenylaziridine, mol wt 147)
could also be formed directly from ephedrine by acid dehydration [9].
However, formation from iodoephedrine is more likely. The 'aziridines' can
be reduced to methamphetamine or react to form the impurities found in the
reaction. The 'aziridines' can undergo a ring opening acidic hydrolysis to
form phenyl-2-propanone. The P2P forms an aldol condensation product with
subsequent dehydration to form the 'naphthalene' impurities,
1,3-dimethyl-2-phenylnaphthalene and 1-benzyl- 3-methylnaphthalene [10].
The non-acidic reduction of chloroephedrine produces the 'aziridines' but
no P2P [11,12]. The transient existence of iodoephedrine was detected
indirectly by the total 'aziridines'. The analogous chloroephedrines
undergo thermal decomposition to the 'aziridines' in the injection port of
the gas chromatograph (Martin, W., pers. comm.).


Analysis

Samples from HI/red P laboratories vary from bottled precursors, solids,
single and multiple phase liquids with a pH range of 1-14, to sludges.
Identification of methamphetamine is easily made by direct infrared
analysis on the finished product or acid/base extraction of most samples
with subsequent conversion to the HCI salt. In cases where ephedrine HCI is
present, either from addition as an adulterant or from incomplete
conversion of the original ephedrine, methamphetamine HCl can be separated
by washing the solid with chloroform. The chloroform insoluble portion -
ephedrine HCl, and the chloroform soluble portion - methamphetamine HCI,
can be easily identified by IR. GC/MS can also be used to identify
methamphetamine.

The neutral P2P and 'naphthalene' impurities can be extracted from the
methamphetamine in the original reaction mixture (acidic with HI) or any
other acidic solution in the clandestine laboratory and can be identified
easily by GC/MS techniques.

Ephedrine once exposed to hydriodic acid can form an ion-pair with the
hydriodide. The methamphetamine formed in the reaction also can form an ion
pair with the hydriodide. The HCI and HI salts of methamphetamine are both
insoluble in ether and soluble in chloroform and very soluble in water. The
HI salt is readily soluble in acetone, unlike the HCI salt which is only
slightly soluble. The valuable property of the HI ion-pair is that
methamphetamine HI can be extracted from an aqueous solution with
chloroform. Methamphetamine HCI will not extract into chloroform from an
aqueous solution. The HI salts of the ephedrines also have similar
properties. Methamphetamine HI can be identified by IR from the original
reaction mixture. This method of identification will also work on the
discarded red P sludge. First, an ether wash is required to remove the
neutral P2P and 'naphthalene' impurities. This is followed by a chloroform
extraction. The chloroform extract is evaporated and the light yellow
crystals of methamphetamine HI are identified by IR.

If the HI/red P reaction is incomplete, ephedrine HI or pseudoephedrine HI
can be identified by their IR spectra using the same extraction procedures
given above for methamphetamine HI. Partial conversion will obviously
result in a mixture of the HI salts being obtained. Methamphetamine,
ephedrine, and pesudoephedrine HI salts are light yellow solids at room
temperature. Racemic methamphetamine HI is an oil. The enantiomeric (+) and
(-) salts have identical IR spectra. However, the IR spectrum of the (+,-)
mixture differs from the enantiomers.

Identification of (+)methamphetamine HI indicates that either (-) Ephedrine
or (+)pseudoephedrine was reduced via the hydriodic acid/red phosphorus
method. Identification of P2P and the 'naphthalenes' as impurities also
indicates an ephedrine was reduced under acidic conditions.

The normal screening test for amphetamines is the Marquis reagent which
turns orange to orange/brown. However, the Marquis reagent is not a useful
test for methamphetamine HI. Methamphetamine HI reacts with the reagent to
give an immediate dark brown color with the evolution of iodine. The dark
brown color is caused by the iodine formed from the reaction of sulfuric
acid with iodide ion. Most organic iodides also produce the same reaction
with sulfuric acid. For example, all of the methamphetamine and ephedrine
hydriodides, as well as sodium and potassium iodide, also liberate iodine
with sulfuric acid. The nitroprusside[13] screening reagent can be used to
differentiate methamphetamine (secondary amine, deep blue color) from
amphetamine and dimethylamphetamine (primary and tertiary amines, no
color).

Quantitation of both solid and liquid samples found in HI/red P
laboratories is routinely done by HPLC and GC. The retention times of
compounds are given in Table 1. The enantiomeric form of methamphetamine or
ephedrines is determined by one or more of the following: polarimetry,
mixed microcrystals, mixed melting points, infrared or enantiomeric
derivatization GC techniques.

Analysis of an HI/red P clandestine laboratory in the field presents
hazards. HI is a toxic and strong irritant and contact must be minimized.
Red phosphorus is a flammable/explosive solid and must be handled with
care. Phosphine, a highly poisonous gas, can be produced by careless
heating of the Hi/red P mixture.


Conclusion

The hydriodic acid/red phosphorus reduction of ephedrine to methamphetamine
has been discussed. The stereochemistry of the reaction has been shown as
well as the route of reaction to the impurities and products. Data obtained
from IR spectroscopy and GC/MS spectroscopy have been presented to aid in
the analysis of the precursors, intermediates, impurities, and products.


References

1.      Drug Enforcement Administration, Statistical Reports, 1989.

2.      L. Fieser and M. Fieser, Reagents for Organic Synthesis, Vol. 1,
        Wiley, 1967, p. 449.

3.      C. Buehler and D. Pearson, Survey of Organic Synthesis, Wiley and
        Sons, 1970, p. 7 and p. 332.

4.      H. Emde, Helv. Chim. Acta., 12 (1929) 365.

5.      E. Schmidt, Arch. Pharm., 252 (1914) 89.

6.      E. Ogata, J. Pharm. Soc. Jpn, 451 (1919) 751; Chem. Abstracts 14
        (1920) 475.

7.      S. Menor, Comprehensioe Treatise on Inorganic and Theoretical
        Chemistry, Vol. 11, Longsman, 1922, p. 171.

8.      P. Durrant. Introduction to Advanced Inorganic Chemistry, Wiley and
        Sons, 1962, p. 710.

9.      N. Auterhuff, Ongew Chem, 67 (1955) 426; Chem. Abstracts, 50. 4826c.

10.     T.S. Cantrell, B. John, L. Jobuson and A.C. Allen, A study of
        impurities pound in methamphetamine synthesized from ephedrine.
        Forensic Sci. Int, 39 (1988) 39-53.

11.     A.C. Allen and W.O. Rinser, Methamphetamine from Ephedrine: 1.
        Chloroephedrines and Aziridines. J. Forensic Sci.. JFSCA, 32 (1987)
        953-982.

12.     T. Rishi, Eisei Kayaku, 29 (1983) 400; Chem. Abstracts, 100, 180174z.

13.     The nitroprusside/sodium nitroprusside) reagent reacts to give a
        deep blue color with secondary amines and has no color change with
        primary and tertiary amines. Ephedrine, a secondary amine, gives a
        faint blue color. The first part of the reagent is prepared by
        mixing 25 ml of a one percent sodium nitroprusside solution with 1
        ml acetaldehyde. The second part is a two percent sodium carbonate
        solution. The blue color is formed immediately after the second
        part of the reagent is added.

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