High specific activity (+)-amphetamine and (+)-methamphetamine

Article abstract of DOI:10.1002/jlcr.1659

High specific activity (+)-amphetamine and (+)-methamphetamine were prepared by reductive dechlorination of (S)-(3′,5′-dichlorophenyl)- 2-propylazide and (S)-2′6′-dichloromethamphetamine, respectively. While the latter was readily obtained by resolution o

Full text of DOI:10.1002/jlcr.1659

Research Article
Received 22 January 2009,
Revised 29 April 2009,
Accepted 8 June 2009
Published online 15 July 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1659
High specific activity (1)-amphetamine and
(1)-methamphetamine
Pamela B. Lamb, Charles J. McElhinny, Todd Sninski, Hunter Purdom,
Ã
F. Ivy Carroll, and Anita H. Lewin
High specific activity (1)-amphetamine and (1)-methamphetamine were prepared by reductive dechlorination of
(S)-(30,50-dichlorophenyl)-2-propylazide and (S)-2060-dichloromethamphetamine, respectively. While the latter was readily
obtained by resolution of racemic 2060-dichloromethamphetamine using (1)-dibenzoyltartaric acid, the analogous
amphetamine resisted all efforts to resolve it. Hence, the required chiral precursor was prepared by stereospecific total
synthesis following methodology that had been previously developed in our Laboratories. The tritium labeled compounds
had specific activity 30.1 Ci/mmol and 38.3 Ci/mmol, respectively.
Keywords: (S)-amphetamine; tritium; (S)-methamphetamine; high specific activity
Introduction
Results and discussion
Amphetamine (1) and methamphetamine (2) are extensively In order to provide (S)-amphetamine [(S)-1] and methamphe-
implicated in CNS activity and the stereoselectivity of the tamine [(S)-2] labeled at metabolically stable sites, labeling of
optical antipodes has been well documented. In general, the (S)- the aromatic moiety was preferred. Reductive dehalogenation
(1)-enantiomers of amphetamine [(S)-1] and methampheta- under tritium is a simple, well-known method for introducing
mine [(S)-2] have been demonstrated to have about five times tritium onto aromatic moieties. Thus, ring-halogenated (S)-
greater psychostimulant activity than the (R)-(ꢀ)-forms [(R)-1 amphetamine and (S)-methamphetamine were required. In
and (R)-2]. In a recent study of the effects of (S)- and (R)- general, aromatic bromides and iodides are used, since they
methamphetamine in humans,1 the pharmacokinetic para- are known to be much more reactive than aromatic chlorides.5–9
meters for the enantiomers administered separately were found However, our proposed method of synthesis (Scheme 1) was
to be similar, but the elimination half-life was longer for incompatible with these substituents. Since we had successfully
(R)-methamphetamine, and it did not increase the systolic utilized a slight modification of a published procedure10 to
blood pressure like (S)-methamphetamine. Interestingly, reductively tritiate aromatic chlorides, (S)-20,60-dichloroamphe-
(R)-methamphetamine was psychoactive, producing intoxication tamine [(S)-3] and (S)-20,60-dichloromethamphetamine [(S)-4]
and drug-liking ratings similar to those for (S)-methampheta- were targeted as tritiation precursors.
mine at the same dose. However, despite the longer half-life
Following well-established methodology, commercially avail-
of (R)-methamphetamine, its effects were dissipated twice as able 2,6-dichlorobenzaldehyde (5) was converted to 20,60-
fast as those of (S)-methamphetamine. Investigation of amphe- dichlorophenyl-2-nitropropene (6)11 and the latter was reduced
tamine binding sites has been hindered by the lack of to racemic 20,60-dichloroamphetamine (3) (Scheme 1). The
the separate antipodes, (S)- and (R)-, of amphetamine [(S)-1 secondary amine, racemic 4, was prepared by carbamoylation
and (R)-1] and methamphetamine [(S)-2 and (R)-2] with of 3 to give the methyl carbamate 7 followed by reduction
high specific activity. Thus, it has been reported that, using (Scheme 1). Attempted resolution of 20,60-dichloroamphetamine
(1)-[3H]amphetamine (specific activity 15.7 Ci/mmol), binding (3) using (1)-tartaric acid, based on reported methodology for
sites with apparent affinity constants of 96 and 279 nM were amphetamine (1),12 was not successful. Use of camphoric acid or
detected in hypothalamic membrane preparations from rat dibenzoyltartaric acid also failed to resolve 3. On the other hand,
brain,2 but this has been challenged as artefactual, resulting treatment of 4 with (1)-dibenzoyltartaric acid resulted in an
from inadequate filtration technique.3 Data obtained using both
filtration and centrifugation techniques in a follow up investiga-
tion were consistent with the presence of a binding site for
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O.
(S)-1, but could neither confirm nor exclude the presence of a Box 12194, Research Triangle Park, NC 27709, USA
second binding site.4 As part of our NIDA supported program to
provide useful biochemical tools to researchers, we synthesized
higher specific activity (430 Ci/mmol) (S)-amphetamine [(S)-1]
and (S)-methamphetamine [(S)-2].
*Correspondence to: Anita H. Lewin, Center for Organic and Medicinal
Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park,
NC 2709-2194, USA.
E-mail: ahl@rti.org
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Copyright r 2009 John Wiley & Sons, Ltd.

P. B. Lamb et al.
Scheme 1.
Scheme 2.
optically pure salt after recrystalization. Determination of optical
purity was performed by HPLC analysis of the urea formed by
reaction with (R)-a–methylbenzylisocyanate with the dibenzoyl-
tatrate salt of 4 in the presence of triethylamine.13 Thus, while
the urea from racemic 4 clearly showed the presence of two
diastereomers, the urea from the dibenzoyltatrate salt of 4
(4.DBT) showed only a small amount (o3%) of the later eluting
diastereomer. Additional confirmation of the chirality and of the
chiral integrity of 4.DBT was obtained by reductive dehalogena-
tion of 4.DBT and analysis of the resulting methamphetamine
(2). HPLC analysis of the urea formed by reaction of the
dehalogenation product with (R)-a–methylbenzylisocyanate
showed the main component (97.6%) to coelute with the urea
formed when (R)-a–methylbenzylisocyanate was reacted
with authentic (S)-methamphetamine [(S)-2]. Reductive dehalo-
genation of (S)-20,60-dichloromethamphetamine (4) was accom-
plished using a slight modification of the published procedure.10
Thus, we used tetrahydrofuran as the reaction medium to
minimize tritium–hydrogen exchange (and increase the specific
activity) and used 20% palladium hydroxide on carbon,
triethylamine, and a few drops of methanol to effect the
tritiation at slightly reduced (650 Torr) pressure. A 6% yield of
tritium labeled (S)-methamphetamine ([3H(n)]-2) with specific
activity 38.3 Ci/mmol was recovered after purification.
Attempts to obtain (S)-1 by demethylation of (S)-214 were not
successful. Since it appeared that secondary amphetamines are
more readily resolved than their primary counterparts, the
Scheme 3.
N-benzyl analog of 4 was prepared by benzoylation of 3 appropriate phenylacetone (8) with (S)-a-methylbenzylamine
followed by reduction. This compound failed to afford salts with (9), separation of the (S,S)-diastereomer 11 by fractional
tartaric acid, dibenzoyltartaric acid, and camphoric acid, crystallization, and debenzylation (Scheme 2),17 (b) elaboration
suggesting that the benzyl moiety reduced the basicity of the of chiral propylene oxide (14) to chiral phenyl-2-propanol (15),
nitrogen to the point that it failed to deprotonate these acids.
followed by conversion of the hydroxyl functionality to an amine
In light of these difficulties, the preparation of a suitable (3) (Scheme 3).18 While option (a) is certainly shorter, it can
precursor by total synthesis was undertaken. Although novel become quite tedious when the required phenylacetone 8 must
approaches to the preparation of chiral amines by transfer be synthesized.
hydrogenation15,16 of chiral imines have recently been reported,
We pursued option (b), targeting 17a as the tritiation
none have been documented for the preparation of chiral precursor to (S)-3. Reaction of commercially available 3,5-
amphetamines. The two specific routes to amphetamines are: (a) dichlorobromobenzene (12a) with butyl lithium at low tem-
formation of a diastereomeric mixture by condensation of the perature followed by reaction with (R)-propylene oxide (14)
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J. Label Compd. Radiopharm 2009, 52 457–462

P. B. Lamb et al.
20,60-Dichlorophenyl-2-nitropropene (6)
gave a mixture of two alcohols. Mass spectral analysis showed
that one was the desired alcohol 15a; the second alcohol
contained a single chloro substituent along with a bromo
substituent and was presumed to be 30-bromo-50-chlorophenyl-
2-propanol (15b). To obtain tritium labeled (S)-1 either alcohol,
or a mixture of the two alcohols, could have been used.
However, we preferred to isolate the major fraction so that all
intermediates could be well characterized. Column chromatogra-
phy gave an oil with nuclear magnetic resonance (NMR) and mass
spectral data consistent with the desired 30,50-dichlorophenyl-2-
propanol (15a). This alcohol was found to be499% ee by gas
chromatographic (GC) analysis of the methyl chloroformate (MCF)
derivative. The alcohol 15a was converted to the corresponding
tosylate 16a by reaction with tosyl chloride in pyridine.
Displacement with sodium azide gave 17a. Catalytic reduction
of 17a using conditions that had been found to be effective
for the reductive dechlorination of (S)-4 (Pd(OH)2/C in THF,
650 mm H2) gave a mixture of products containing 1. Mass
spectral analysis indicated the byproducts to be partially reduced
materials. Eventually, it was found that a cleaner reaction product
could be obtained using palladium catalyst activated by hydrogen
depletion19 in triethylamine as solvent. Analysis of the product by
A solution of 2,6-dichlorobenzaldehyde (5) (100 g, 0.571 mol)
and ammonium acetate (48.4 g, 0.628 mol) in nitroethane
(700 mL) was refluxed for 16 h. After cooling to room
temperature, the solution was poured over 60 mL ice water,
extracted with Et2O, dried over Na2SO4 and evaporated. The
resulting oil was dissolved in Et2O, washed sequentially with
H2O, sat. NaHCO3 and H2O, dried over Na2SO4 and evaporated
to a yellow oil. Crystallization from absolute EtOH gave pale
yellow crystals (118 g, 81%), m.p. 48–491C (Ref.1. 48–491C).
1H NMR (250 MHz, CDCl3) d (ppm): 2.12 (s, 3H, CH3), 7.31
(t, J = 6.2 Hz, 1H, ArH), 7.34 (d, J = 8.1 Hz, 2H, ArH), 7.83 (s, 1H,
ArCH = C).
20,60-Dichloroamphetamine Methylcarbamate (7)
To a stirred slurry of LiAlH4 (11.45 g, 0.34 mol) in dry Et2O
(500 mL) was added dropwise a solution of 20,60-dichlorophenyl-
2-nitropropene (6) (11.65 g, 0.05 mol) in Et2O (250 mL). The
mixture was refluxed for 8 h, cooled to room temperature and
stirred overnight. The reaction was quenched by the dropwise
addition of H2O (11.45 mL), 15% NaOH (11.45 mL), and H2O
(34.35 mL). The white salts that resulted were removed by
filtration, and washed with Et2O. The filtrate was dried over
Na2SO4 and evaporated to give 20,60-dichoroamphetamine (3) as
a yellow oil (10.61 g). 1H NMR (250 MHz, CDCl3) d (ppm): 1.18
(d, J = 6.4 Hz, 3H, CHCH3), 1.39 (bs, 2H, NH2), 3.0 (dd, 2H,
ArCH2CH), 3.3 (m, 1H, ArCH2CH), 7.07 (t, J = 7.4 Hz, 1H, ArH), 7.3
(d, J = 8 Hz, 2H, ArH). Conversion to the methylcarbamate 7 was
carried out by the addition of a solution of MCF (7.59 mL,
0.10 mol) in Et2O (100 mL) to a solution of 20,60-dichloroamphe-
tamine (3) (12.22 g, 0.06 mol) in Et2O (50 mL) containing Na2CO3
(53.51 g). After stirring overnight the mixture was washed with
1N NaOH (400 mL), 1N HCl (100 mL), and H2O (200 mL). The Et2O
phase was dried over Na2SO4, filtered and evaporated to a white
solid (ꢂ12 g). Recrystallization from hot hexane (200 mL) gave 7,
GC showed it to coelute with
a reference standard of
amphetamine and further GC analysis of the (S)-(-)-N-(trifluoroa-
cetyl)prolyl chloride (TPC) derivative showed the product to be
98% ee and to coelute with the TPC derivative prepared from
(S)-(1)-amphetamine. It follows that displacement of the tosyl
group by azide proceeded with inversion of configuration, as
expected18 to afford azide 17a with S-configuration. Reduction of
17a under tritium gas under the same conditions afforded the
product [3H(n)]-1 in 38% yield. Three preparative TLC purifications
were required to achieve 495% chemical and radiochemical
purity. The pure product was recovered in 12% yield and had
specific activity 30.1Ci/mmol.
Experimental
1
10.01 g (64%), m.p. 83–841C, H NMR (300 MHz, CDCl3) d (ppm):
0.99 (d, J = 6.6 Hz, 3H, CHCH3), 3.03–3.20 (m, 2H, ArCH2CH), 3.40
(s, 3H, OCH3), 4.10–4.18 (m, 1H, ArCH2CH), 7.17 (t, J = 7.5 Hz, 1H,
ArH), 7.30 (d, J = 8.1 Hz, 2H, ArH). Anal. Calcd for C11H13Cl2NO2: C
50.40; H 5.00; N 5.34. Found: C 50.50; H 4.97; N 5.28.
Proton NMR spectra were recorded on either a Bruker AM-
250 MHz or a Bruker Avance 300 MHz NMR spectrometer, as
indicated. MS were determined on a Perkin-Elmer Sciex API
150EX mass spectrometer outfitted with an APCI source. TLC
analyses were carried out on commercial pre-coated silica gel
60F254 glass plates (E. Merck: 5 ꢁ 20 cm). GC analyses were
performed on a HP 5890 Gas Chromatograph equipped with
FID detector, split/splitless injection port, a HP5 column (cross-
linked 5% PhMe Siloxane; 30 m ꢁ 0.32 mm ꢁ 0.25 mM film
thickness), Nitrogen as a carrier gas, injection port 3001C, and
Detector 3001C; additional conditions are in the text. The HPLC
analyses were performed on a dual pump system (Waters 515
solvent delivery system) equipped with a Waters U6K injector, a
Rainin UV–Vis detector, and a IN/US Systems b-RAM radio-
detector connected after the UV–Vis detector, controlled by
IN/US B2 version 3.03/BRSA version 2.1 software. HPLC column
and other analysis details are shown in the text. The water
used in HPLC analyses was obtained from a Millipore Milli-Q
Plus Ultra-Pure Water System. Radioactive samples were
(S)-20,60-Dichloromethamphetamine (S-4) hydrochloride
A solution of 7 (9.91 g, 0.04 mol) in Et2O (300 mL) was added
dropwise over a period of 90 min to a stirring solution of LiAlH4
(19.13 g, 0.05 mol) in Et2O (600 mL). The reaction mixture was
stirred for 4 h, and then quenched with H2O (19.13 mL), 15%
NaOH (19.13 mL), and H2O (57.39 mL). Periodically, Et2O had to
be added to keep the mixture stirring. The solids were removed
by filtration. The filtrate was dried over Na2SO4 and evaporated
1
to give 4 as a pale yellow oil (8.03 g, 92%). H NMR (300 MHz,
MeOD) d (ppm): 1.28 (d, J = 6.3 Hz, 3H, CCH3), 2.80 (s, 3H, NCH3),
3.28–3.42 (m, 2H, ArCH2CH), 3.61–3.65 (m, 1H, ArCH2CH), 7.29
(t, J = 7.2 Hz, 1H, ArH), 7.50 (d, J = 7.8 Hz, 2H, ArH). To resolve the
racemic product a solution of 20,60-dichloromethamphetamine
(4) (2.00 g, 0.009 mol) in absolute EtOH (40 mL) was treated with
(1)-dibenzoyl tartaric acid (4.60 g, 0.013 mol). After 4 h, the
precipitated solid was collected (2.3 g) and recrystallized from
hot absolute EtOH (50 mL) to give the (1)-dibenzoyl tartrate of 4
(4.DBT) as a white solid, (1.45 g). Optical purity was determined
counted using
a
Tri-Carb Liquid Scintillation Analyzer
(Packard Bioscience model 2100TR) utilizing IN-FLOW 3 (IN/US
Systems) as the liquid scintillation counting cocktail. Melting
points were determined using a Fisher–Johns melting point
apparatus.
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P. B. Lamb et al.
by HPLC analysis of the urea formed as follows: (R)-(1)-a- TLC-radioscan, as above). The specific activity was determined
methylbenzylisocyanate (4 mL) followed by Et3N (6–7 drops) was by GC (as above). (1)-Amphetamine HCl (Rt 5.23min) was used as
added to a suspension of 4.DBT (50–100 mg) in dry THF (0.5 mL). the internal standard. The specific activity was found to be
The sample was analyzed using a Radial Pak silica gel cartridge, 38.3Ci/mmol; 257.4 mCi/mg.
eluting with isooctane:iPrOH:HOAc 95:4.5:0.5 at 1 mL/min and
detecting at 254 nm. For racemic 4 this analysis resulted in two (R)-(30,50-Dichlorophenyl)-2-propanol (15a)
signals of equal areas, with Rt 11.15 and 13.87 min. For the
A solution of 1-bromo-3,5-dichlorobenzene (12) (7.5g; 0.033 mol)
isolated 4.DBT, the later eluting peak was 497%. Further
in dry THF (150mL) in a three necked flask equipped with a
authentication of optical purity was obtained by treatment of a
thermometer, dropping funnel and a septum, was stirred and
cooled under nitrogen in an N2 (l)/hexane slush bath. At ꢀ941C,
n-BuLi (16.6 mL; 0.033 mol 2 M in pentane) was slowly added
solution of 4.DBT (900 mg, 1.56 mmol) in MeOH (20 mL) with
20% Pd(OH)2/C (0.42 g), sparging with N2(g) and stirring under
H2(g) overnight at reduced pressure. The catalyst was removed
using a dropping funnel. After stirring 10min, propylene oxide
by filtration and the filtrate was evaporated to a residue that was
(14) (0.96 g, 0.017 mol) was slowly added. After stirring 15min,
dissolved in CH2Cl2 (50 mL). The solution was washed with 1N
BF3Et2O (3.53 g; 0.025 mol) was added via syringe. The solution
NaOH (50 mL) and H2O (100 mL). The CH2Cl2 extract was dried
was stirred for 15min and then quenched with saturated NH4Cl.
over Na2SO4 and evaporated to an oil. The oil was dissolved in
The solution was extracted with ether (3ꢁ 50mL). The combined
organic extract was dried over Na2SO4, filtered, and the solvent
MeOH and evaporated to ensure that all the CH2Cl2 had been
removed. The oil was dried on a vacuum pump for 0.5 h. Analysis
by GC (951C isothermal, carrier flow 1.8 mL/min; Rt 6.87 min)
confirmed that the product was methamphetamine (2).
was evaporated. The residual yellow oil was chromatographed
and the product-containing fractions (1:3 SiO2 EtOAc-hexane, Rf
0.24) were combined and evaporated to give 15a as a light
HPLC analysis of the urea formed with (R)-(1)-a-methylbenzyl-
yellow oil (0.85 g, 25%). GC analysis of the MCF derivative (HP-5
isocyanate as above and using the above HPLC conditions
column- 2151C, isothermal) showed the optical purity of 15a (Rt
showed a standard of racemic methamphetamine to have two
peaks with equal areas and Rt 17.47 and 19.84 min; analogous
analysis of the reductive dehalogenation product showed
1
9.960 min.) to be499%. H NMR (300MHz, CDCl3) d (ppm): 1.25-
(d, J = 6 Hz, 3H, CHCH3), 2.65–2.76 (m, 2H, ArCH2CH), 3.99–4.07
(m, 1H, ArCH2CH), 7.31 (d, J = 9 Hz, 2H, ArH), 7.39–7.46 (t, J = 9 Hz,
the later eluting material (497%) to coelute with standard
(1)-methamphetamine (Rt 20.96 min). To prepare the hydro-
1H, ArH), M/Z calcd for C9H10Cl2O, 204.2; found 204.15.
chloride salt a suspension of 4.DBT (2.9 g. 0.005 mol) in 4 N
NaOH (20 mL) was extracted with ether (3 ꢁ 20 mL). The
combined extract was dried over anhydrous Na2SO4 and
(S)-(30,50-Dichlorophenyl)-2-propyl Azide (17)
A solution of (R)-30,50-dichlorophenyl-2-propanol (15b) (790mg,
concentrated. The residual oil (0.98 g) was taken up in ether
(30 mL) and HCl gas was bubbled in. After overnight at ambient
temperature the precipitated solid was collected and dried
under vacuum (1.00 g, 78%). M.p. 200–2021C; 1H NMR (300 MHz,
MeOD) d (ppm): 1.08 (d, J = 9 Hz, 3H, CCH3), 2.80 (s, 3H, N CH3),
3.36–3.42 (m, 2H, CH2), 3.61–3.65 (m, 1H, CH), 7.31 (t, J = 4.5 Hz,
1H, ArH), 7.47 (d, J = 4.5 Hz, 2H, ArH); Anal. calcd. for C10H14Cl3N:
C,47.18; H 5.54; N 5.50. Found: C 47.42; H5.58; N 5.43.
3.85mmol) in pyridine (20 mL) was stirred in an ice bath and
p-toluenesulfonyl chloride (880mg, 4.62mmol) was added. After
stirring to mix, the solution was placed in the freezer. After three
days the crystals that formed were removed by filtration and the
solution was added to a cold biphase of 3% NaOH (100mL) and
CHCl3 (75mL). The layers were separated and the aqueous phase
was re-extracted with cold CHCl3 (75 mL). The combined organic
extract was washed with cold aqueous 2% HCl (100 mL), dried
over anhydrous Na2SO4, and concentrated to give (R)-(30,50-
dichlorophenyl)-2-propyl tosylate (16) (1.27 g mg, 92%: m.p.
77–811C. 1H NMR (300MHz, CDCl3) d (ppm): 1.24–1.26 (d,
J = 6 Hz, 3H, CHCH3), 2.43 (s, 3H, ArCH3), 2.70–2.77 (m, 2H,
ArCH2CH), 4.61–4.68 (m, 1H, ArCH2CH), 6.86 (s, 2H, ArH) 7.12 (s,1H,
ArH), 7.18 (d, J = 6 Hz, 2H, ArH), 7.54 (d, J = 6 Hz, 2H, ArH). To form
the azide, NaN3 (880mg; 13.5mmol) was added to a solution of
16 (1.22 g; 0.003 mol) in DMF (5 mL) and the solution was stirred
under N2 at room temperature for three days. The reaction was
quenched with H2O, and extracted into Et2O (3 ꢁ 30mL). The
combined extract was washed with water, then dried over
Na2SO4, filtered and concentrated. The residual oil was dried
in vacuo overnight and then purified by column chromatography
(SiO2, 4:1 hexane/EtOAc). The product-containing fractions were
combined and evaporated to yield 17 as a yellow oil that was
dried on the pump (570mg, 72%). 1H NMR (300MHz CDCl3) d
(ppm): 1.29 (d, J = 6 Hz, 3H, CHCH3), 2.66–2.78 (m, 2H, ArCH2CH),
3.66–3.72 (m, 1H, ArCH2CH), 7.10 (s, 2H, ArH), 7.26 (s, 1H, ArH),
M/Z calcd for C9H9Cl2N3 (m-2N11) 204.2; found: 204.3.
(S)-(1)-[20,60-3H(n)]Methamphetamine [3H(n)]-(2)
A
solution of (S)-20,60-dichloromethamphetamine (S-4) HCl
(10.58mg; 0.042 mmol) in THF (0.5mL) containing 10 drops
MeOH and Et3N (100mL) was pretreated with 20% Pd(OH)2/C
(9.83 mg) and filtered through a celite plug into a 2 mL tritiation
flask containing 20% Pd(OH)2/C (10.64mg). The catalyst was
washed with THF (0.5mL) and the wash was added to the
reaction vessel. The mixture was stirred under tritium gas
overnight at reduced pressure. Tritium uptake was 4.54Ci. The
catalyst was removed by filtration and washed with MeOH. The
combined filtrate and washings were concentrated under
vacuum. The residue was stirred in MeOH and phosphate buffer
pH 11.2 to remove labile tritium. The solution was extracted with
CH2Cl2 (4ꢁ 30mL), and the extract was dried over anhydrous
Na2SO4. TLC radioscan of this material (SiO2, EtOAc-CH2Cl2-MeOH-
NH4OH 15:10:4:0.5, Rf 0.19) showed the mixture to contain 60% of
2, and 40% of two impurities. The impure product was streaked
onto two 20ꢁ 20cm SiO2 plates, 25mm, F-254 nm and eluted
with EtOAc-CH2Cl2-MeOH-NH4OH 15:10:4:0.5, Rf 0.19. The band
corresponding to 2 was removed and extracted with EtOH.
The extract was filtered through a nylon syringe filter into
a volumetric flask containing EtOH (95 mCi, 98% pure by
Reduction of the azide 17 to amphetamine (1a)
A solution of 17 (14.7 mg, 0.06 mol) in Et3N (0.5 mL) was
pretreated with hydrogen-depleted19 10%Pd/C (15 mg). The
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P. B. Lamb et al.
catalyst was removed by filtering the mixture through a syringe as above. The band corresponding to amphetamine (1) (Rf 0.3)
filter into a 2 mL round bottomed flask containing a stir bar and was removed and eluted with EtOH. The extract was filtered
fresh hydrogen-depleted 10%Pd/C (14.9 mg). The collected through a nylon frit into a 250 mL volumetric flask and diluted to
catalyst was washed with additional Et3N (0.5 mL) that was the mark with EtOH. An aliquot was removed and counted
added into the tritiation flask. The material in the flask was showing a recovery of 232 mCi. TLC radioscan of the purified
stirred under H2 for 48 h. The reaction mixture was filtered material on SiO2 and eluting in EtOAc-CH2Cl2-MeOH-NH4OH
through a celite plug into a vial and the solvent was removed [15:10:4:2] (Rf 0.35) and in EtOAc-Hxn-EtOH-NH4OH [60:25:14:1]
under a stream of N2. The residue was dissolved in H2O (3 mL), (Rf 0.13) showed the purity to be 96.6%. However, a purity
acidified with 0.2 N HCl, and the solution was washed with Et2O. check using HPLC b-Ram (Waters C18 Nova-Pak column, MeOH-
The aqueous phase was basified with NH4OH and extracted with H2O (3.5 g/L ammonium carbonate, 75:25, Rt 4.34 min) showed
Et2O. The ether extract was dried over Na2SO4 and filtered the purity to be only 91.9%. Forty-six millicuries were removed
through a syringe filter into a tared vial. The ether was removed for the stock solution and concentrated. The residue was
under a N2 stream and the residue was dried overnight under streaked into
a 20 ꢁ 20 cm SiO2 plate and eluted with
vacuum (7.45 mg, 100%). The oil was dissolved in CH2Cl2 (1 mL) EtOAc-CH2Cl2-MeOH-NH4OH 15:10:4:1, Rf 0.13. The area sur-
and 10 mL was analyzed by GC: 701C isothermal, carrier flow rounding the Rf of unlabeled 1 was removed and the material
1.8 mL/min; Rt 11.98 min (coeluted with standard ampheta- was extracted into EtOH. The extract was filtered into a
mine). To determine the chiral integrity the TPC derivative was 25 mL volumetric flask and filled to the mark with EtOH.
prepared by adding a solution of the product (3.73 mg) in CHCl3 Counting of an aliquot indicated a recovery of 14.5 mCi. The
(0.5 mL) to 1 mL of a 0.1 M solution in CH2Cl2, (97% by GLC, purity of this material was495% (HPLC b-Ram as above). The
Sigma-Aldrich) followed by the addition of one drop Et3N. After specific activity was determined to be 30.1 Ci/mmol; 223.3 mCi/
10 min 6N HC (2 mL) was added and the phases were separated. mg using GC (951C; isothermal; carrier flow at 1.8 mL/min, Rt
The organic phase was dried with a small amount Na2SO4. The 5.23 min) with (1)-methamphetamine HCl (Rt 6.87 min) as the
solution was pipetted into a vial and the solvent was removed internal standard.
under a stream of nitrogen. Similarly the TPC derivative of
standard (1)- and (-)-amphetamine were prepared. After the
Conclusions
samples were dried under vacuum they were dissolved in
CH2Cl2. (0.1 mL) and analyzed by GC (program: 100 to 2801C at
51C/min and holding 5 min with the carrier flow at 1.8 mL/min).
The retention time of the TPC derivative of the (1)-ampheta-
mine standard was 21.45 min and the retention time of the TPC
derivative of (-)-amphetamine standard was 20.81 min. The TPC
derivative of the product had retention time 21.36 min with a
very small peak (4% by area) with retention time 20.79 min.
Since the derivatizing agent was 97% ee, this indicated that the
product was 98% ee.
(S)-(30,-50-dichlorophenyl)-2-propyl azide and (S)-20,60-dichloro-
methamphetamine have been prepared as precursors suitable
toward the preparation of relatively large amounts (470 mCi) of
tritium labeled (1)-amphetamine and (1)-methamphetamine.
Reduction of these precursors has afforded the products in 38
and 6% yield, respectively, and with high specific activity
(430 Ci/mmol).
Acknowledgement
(S)-(1)-[30,50-3H(n)]Amphetamine ((S)-1[3H(n)]-1c))
The authors gratefully acknowledge Contracts No. NO1-DA-3-
7736 and NO1-DA-8-7763 from NIDA for supporting this
work.
A
solution of (S)-30,50-dichlorophenyl-2-propylazide (17),
(14.7 mg; 0.0638 mmol) in dry Et3N (0.5 mL) was pretreated with
hydrogen-depleted19 10%Pd/C (15 mg) for 15 min. The mixture
was filtered through a nylon frit into a 2 mL tritiation flask
containing hydrogen-depleted 10%Pd/C (15.42 mg). The catalyst
was washed with Et3N (0.5 mL) and the washing was added to
the reaction vessel. The solution was stirred under tritium gas for
5 h and then filtered through celite into a small round-bottomed
flask. The amount of tritium used was 4.72 Ci. The reaction
solvent was removed by vacuum distillation and the residue was
dissolved in H2O (3 mL). The solution was treated with 0.2N HCl
(1 mL) and extracted into Et2O. The aqueous phase was basified
to pH 9 with NH4OH and extracted with Et2O. Spotting onto a
TLC plate and radioscanning (without elution) indicated that
both extracts contained radioactivity. Most of the Et2O was
removed from each extract and the residues were each
reconstituted in EtOH. An aliquot was removed from each and
counted. The organic extract from the acid wash contained
111 mCi. The organic extract from the base wash contained
738 mCi. TLC-radioscan of each (SiO2, EtOAc-Hxn-EtOH-NH4OH
60:25:14:1) showed tritiated amphetamine (1) to be present in
the organic extract from the base wash. The solvent was
concentrated and the residue was streaked onto 2–20 ꢁ 20 cm
SiO2 plates 0.25 mm, F-254 nm and eluted with the same solvent
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