法科学技術，13(1)，67―72(2008) 67

―Technical Note―

Convenient Method for Synthesis of l -Methamphetamine

Shinobu Hazama1, Satoshi Ichikawa2 and Fumihiro Yonebayashi3

Forensic Science Laboratory, Hokkaido Prefectural Polise H.Q.1

Nishi 7, Kita 2, Chuuou-ku, Sapporo 0608520, Japan.
Graduated School of Pharmaceutical Sciences, Hokkaido University2.
Nishi 6, Kita 12, Kita-ku, Sapporo 0600812, Japan
Forensic Science Laboratory, Hokkaido Kushiro Area Police H.Q.3
105 Kurogane-cho, Kushiro 0858511, Japan.

(Received 27 March 2007; accepted 27 July 2007)

Enantioselective analysis of methamphetamine (MA) and amphetamine (AP)

is necessary in forensic drug analysis. In general, standard materials are required for
performing forensic investigation and also for developing new analytical methods.
However, l-MA is not commercially available in Japan and only a few reports are
available on the enantioselective synthesis of l-MA. We developed a new and
convenient method for the synthesis of l-MA using d-norephedrine (d-NE) as a
starting material. d-NE was treated with 1,1′ carbonyldiimidazole to produce the
corresponding cyclic carbonate, and the product was treated with sodium hydride
and iodomethane to form mono-N-methylated amine derivative, which was treated
with palladium on activated carbon in hydrogen atmosphere for catalytic reduction.
After the addition of aqueous hydrogen chloride (HCl), l-MA was obtained as its
HCl salt (total yield 58).

Key words : Synthesis, l-methamphetamine, d-norephedrine

Introduction Parkinson's disease )2) . Furthermore, MA

Methamphetamine ( MA ) and products produced from clandestine laboratories
amphetamine (AP) are strong central nervous sometimes contain both enantiomers. The ratio
system stimulants. The use of these drugs is of these enantiomers provides information about
strictly regulated in Japan. Every year, many the source and synthetic route of MA.
people are arrested for the use and/or possession Therefore, the analysis of the enantiomeric ratio
of MA in Japan1), making it the most important of MA is very important, and many analytical
drug in the ˆeld of forensic science. Since MA methods have been developed37).
and AP have an asymmetric carbon, they have Authentic MA is required as a standard
two optically active isomers, d- and l-forms. material for enantiomeric analysis and for
Although the d-isomer ((S)(＋)MA) is developing new analytical methods. Although d-
widely abused, the Vicks Vapor Inhaler, which is MA is commercially available, l- and dl-MA can
available as over-the-counter drug in USA, not be supplied in Japan. Consequently, for the
contains (R)(－)MA (l-MA)2). Moreover, l- above mentioned purposes, it is necessary to
MA is a metabolites of l-deprenyl (a drug for synthesize l-MA. A few studies reported on the
68 Shinobu Hazama et al.

synthesis of MA from ephedrine (EP)8), phenyl ‰ow of carrier gas (helium) was maintained at
2 propanone ( P2P )9) , and phenylalanine 1.0 ml / min in constant ‰ow mode. The
(PHE)10). EP is easily prepared from natural temperature of injection port and detector was
products such as ephedra plants, and natural EP 250° C, and the split ratio was 501.
is in the l-form ((1S, 2R)(－)EP), which has Gas chromatography-mass spectrometry
the same stereochemical conˆguration as d-MA (GC/MS) was performed with Shimadzu model
at the C2 position. To obtain l-MA with this GCMS-QP5050A (Shimadzu, Kyoto, Japan),
method, as a starting material it is necessary to equipped with a Class 5000 data processing
use (1R, 2S)(＋)EP (d-EP), which is not system. The analytical column was BETA
commercially available in Japan. Synthesis of DEXTM 225 (30 m×0.25 mm id, 0.25mm thick
MA from P2P causes its racemization. PHE can ˆlm; Supelco, Inc., Bellefonte, PA, USA).
be used to synthesize MA enatioselectively; Temperature conditions were as follows: initial
however, this method is complicated. Instead, temperature was 80° C, which was increased to
(1S, 2R)(＋)norephedrine (d-NE), which has 200° C at 5°
C/min and held for 6 min. The ‰ow of
a structure similar to d-EP, is commercially carrier gas (helium) was maintained at 1.0 ml/
available. In this study, d-NE was chosen as a min in constant ‰ow mode. The temperature of
starting material, and an convenient method was the injection port and transfer line was 250° C
developed for the enantioselective synthesis of l- and 280° C, respectively, and the split ratio was
MA. 101. Mass spectra were obtained by electron
ionization mode at an ionization energy of 70 eV
Materials and Methods in the scanning mode.
1. Reagents Melting point was recorded on a MP500D
d-MA hydrochloride and dl-AP sulfate were melting point apparatus (Yanaco, Kyoto,
purchased from Dainippon Pharmaceutical Japan). Optical ratios were measured on a P
(Osaka, Japan) and Takeda Pharmaceutical 10303 polarimeter (Jasco, Tokyo, Japan).
(Osaka, Japan), respectively. d-NE, l-NE, Fourier transform infrared spectrophotometry
palladium on activated carbon (Pd/C), 1 M (FTIR) analysis was measured on a FTIR
hydrochloric acid (HCl), and Celite (No. 500) 8600PC (Shimadzu, Kyoto, Japan). EI-MS
were purchased from Wako Pure Chemicals (positive ion mode) and FAB-MS (positive ion
Industries (Osaka, Japan). Sodium hydride mode; matrix: 4nitrobenzyl alcohol) spectra
(NaH), iodomethane (MeI), and tri‰uoroacetic were obtained on a JMS-FABmate (JEOL,
anhydride (anhydrous TFA) were purchased Tokyo, Japan) and a JMS-HX110 instruments
from Kanto Chemical (Tokyo, Japan). 1,1′  (JEOL), respectively.
Carbonyldiimidazole was purchased from 3. Chromatographic analysis
Aldrich (Steinheim, Germany). Other solvents To monitor synthetic reactions and estimate
were used as reagent grade. optical purities, GC and GC/MS analysis were
2. Instruments performed, respectively. Samples for GC and
Gas chromatography (GC) was performed GC/MS analysis were prepared as follow. In GC
with a HP 6890 series (Hewlett-Packard, Palo analysis, each reaction mixture, with
Alto, CA, USA), equipped with a hydrogen concentration of approximately 1 (w/v), was
‰ame ionization detector. The analytical column injected (reaction A), after quenching with
was DB1 (30 m×0.25 mm id, 0.25mm thick methanol (MeOH) (reaction B) or being ˆltered
ˆlm; J&W Scientiˆc, Rancho, Cordova, CA, ( reaction C ) . In GC / MS analysis, the
USA). Temperature conditions were as follows: dichloromethane (CH2Cl2 ) solution containing
initial temperature was 130° C, which was d-NE and compound 4 (1 mg/ml) was mixed
increased to 190°C at the rate of 10°
C/min, and with excess anhydrous TFA, and heated at 50° C
was further increased to 280°C at 20°
C/min. The for 15 min. The mixtures were then injected into
 Convenient Method for Synthesis of l-Methamphetamine 69

the GC/MS instrument. (300 ml×2) and brine (300 ml), dried over Na2
4. Experimental SO4, and evaporated under reduced pressure to
( 4R, 5S ) -4-Methyl-5-phenyl-1,3-oxazolidin-2- give crude (3) (1.11 g as a pale yellow crystal, 88
one (2) ): EI-MS m/z (): 57 (100), 191 (65) [M＋],
1,1 ′Carbonyldiimidazole ( 1.17 g, 7.3 58 (41), 176 (18), 147 (17), 117 (11), 132 (10),
mmol) was added to a solution of d-NE (1) (1.0 91 (9), 77 (9), FAB-MS m/z: 192 [M＋H]＋.
g, 6.6 mmol) in CH2Cl2 (100 ml), and the This crude product was used in the next reaction
mixture was stirred at room temperature for 75 without further puriˆcation.
min. H2O (50 ml) was added to the reacting l-Methamphetamine hydrochloride (4)
mixture and stirred constantly to remove excess A mixture of (3) (1.11 g, crude) and Pd on
1,1′-carbonyldiimidazole. The organic layer was carbon (20, 50 mg) in MeOH (100 ml) was
washed with H2O (100 ml×3) and brine (100 vigorously stirred under H2 atmosphere at room
ml), dried over Na2SO4, and evaporated under temperature for 20 h. The mixture was ˆltered
reduced pressure to give crude (2) (1.38 g as a through a Celite pad, and the ˆltrate was
pale yellow crystal, 118): EI-MS m/z (): evaporated under reduced pressure. 1 M aq. HCl
107 (100), 79 (27), 177 (15) [M＋], 77 (9), (10 ml) was added to the residue to form HCl
FAB-MS m/z: 178 [M＋H]＋. This crude salt, and the mixture was evaporated under
product was used in the next reaction without reduced pressure. The residue was puriˆed by
further puriˆcation. recrystallization from diethyl ether-chloroform
(4R, 5S)-3,4-Dimethyl-5-phenyl-1,3-oxazolidin- to give (4) (0.71 g as a white crystal, 66): mp
2-one (3) 173175° C (ref.11) 171173° C); [a]D2215.6°(c
60 NaH (527 mg, 13.2 mmol) was added 1.0, CHCl3 ) (ref. 11 ) [a]D16.3° (c 0.52,
to a solution of (2) (1.38 g, crude) in DMF (100 water)). IR (KBr) cm 1: 2461, 1605, 1489,
－

ml) and the mixture was stirred at room 1456, 1387, 1356, 1082, 1061, 748, 700, 463.
temperature for 30 min. MeI (496 ml, 7.9 mmol) (This spectrum was the same as the spectrum of
was added to the mixture and stirred constantly d-MA hydrochloride). EI-MS m/z (): 58
at room temperature for 30 min. After MeOH (2 (100), 91 (4), FAB-MS m/z: 150 [M＋H]＋.
ml) was added, the mixture was partitioned Anal. Calcd for C10H16ClN: (mol wt. 185.10) C,
between ethyl acetate (300 ml) and H2O (300 64.68; H, 8.68; Cl, 19.09; N, 7.54. Found: C,
ml), and the organic layer was washed with H2O 64.31; H, 8.48; Cl, 19.15; N, 7.48.

Fig. 1 The synthetic scheme of l-methamphetamine hydrochloride from d-norephedrine.

70 Shinobu Hazama et al.

Total yield (in three steps) was 58. to be imidazole (Fig. 2(b)), MeOH (Fig. 2
(c)), and glycerol (Fig. 2(d)). Imidazole and
Results and Discussion glycerol were removed with the washing and
In the earlier reports12,13), the enantiomers recrystallization process, respectively.
of compounds 2 and 3 were prepared from l-NE Furthermore, each reaction could be terminated
and l-EP, respectively, under similar conditions rapidly, except reaction C, and it took only a few
as in reaction A, and compound 2 was obtained days to perform the total reactions. The total
from d-NE treated with diethylcarbonate and yield (58) was satisfactory to obtain authentic
potassium carbonate in good yield (83), standards.
whereas there was no report on the synthesis of Optical purities of d-NE and compound 4
MA from compound 3. In this study, we have were estimated by GC/MS analysis. The total
developed a highly e‹cient enantioselective ion chromatograms are shown in Fig. 3. The
preparation method of l-MA using the retention time and mass spectra of d-NE, d-MA,
commercially available d-NE (1) as the starting and d or l-AP were consistent with those of the
material. Each step was handled with ease and standard materials, and the mass spectra of l-
the obtained materials were in a pure form that NE-bisTFA and d-MA-TFA have the same
was acceptable in the ˆeld of forensic science. In patterns as d-NE-bisTFA and l-MA-TFA,
our method, unreacted reagents were almost respectively. Because commercially available d-
removed by washing with water and by ˆltration, NE material contained trace amount of l-NE as
and a few by-products were formed by an original impurity, it is reasonable that
monitoring with GC analysis. In gas compound 4 contained trace amount of d-MA
chromatograms (Fig. 2), peaks other than those which was derived from l-NE. Furthermore, it
of compounds 14 and solvents were determined contained trace amounts of d or l-AP as

Fig. 2 Gas chromatograms of starting mixture and reaction mixtures.

(a) before reaction A, (b) after reaction A, (c) after reaction B (quenched with MeOH), and (d) after reac-
tion C (ˆltered with membrane ˆlter).
 Convenient Method for Synthesis of l-Methamphetamine 71

Fig. 3 Total ion chromatograms of TFA-derivatives of starting materials (a) and synthetic products (b).
(a) Main peak: d-NE-bisTFA; minor peak: l-NE-bisTFA. (b) Main peak: l-MA-TFA; minor peaks: d-MA-
TFA, d or l-AP-TFA.

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