Synthesis of deuterium labeled standards of 5-methoxy-N,N- dimethyltryptamine (5-Meo-DMT)

Article abstract of DOI:10.1002/jlcr.1109

The Batcho-Leimgruber strategy was employed to synthesize 5-[ ²H₃]-methoxy-1 H-indole 4 from commercially available 5-hydroxy-2-nitrotoluene 1 and CD₃I. Compound 4 was treated with oxalyl chloride, dimethylamine and lithiu

Full text of DOI:10.1002/jlcr.1109

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd. Radiopharm 2006; 49: 897–902.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1109
Research Article
Synthesis of deuterium labeled standards of 5-methoxy-
N,N-dimethyltryptamine (5-Meo-DMT)
Ya-Zhu Xu and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974,
Taiwan, Republic of China
Summary
The Batcho-Leimgruber strategy was employed to synthesize 5-[2H3]-methoxy-1
H-indole 4 from commercially available 5-hydroxy-2-nitrotoluene 1 and CD3I.
Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum
hydride to yield 5-[2H3]-methoxy-N,N-dimethyltryptamine 6. Copyright # 2006 John
Wiley & Sons, Ltd.
Received 6 June 2006; Revised 25 June 2006; Accepted 26 June 2006
Key Words: 5-methoxy-N,N-dimethyltryptamine; phenylethylamine; deuterium labeled;
internal standard
Introduction
Unknown drugs of abuse are typically detected and identified by GC-MS
because of the high sensitivity of this method and its ability to separate
complex mixtures of organic compounds. Based on electron impact (EI), this
technique commonly does not suffice to discriminate among structurally
closely related phenylethylamine drug variants, because of their often almost
identical mass spectra and extremely few molecular and fragment ions,1–4
which adversely influence the ability of the method to detect novel
amphetamine controlled-substance analogs.5,6
The abuse of psychoactive phenylethylamines and phenylisopropylamines
has become a very serious social problem in Taiwan over the last decade.7,8
*Correspondence to: Chinpiao Chen, Department of Chemistry, National Dong Hwa University, Soufeng,
Hualien 974, Taiwan, Republic of China. E-mail: chinpiao@mail.ndhu.edu.tw
Contract/grant sponsor: National Bureau of Controlled Drugs, Taiwan; contract/grant number: DOH94-
NNB-1007
Copyright # 2006 John Wiley & Sons, Ltd.

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Y.-Z. XU AND C. CHEN
Standard samples for analyzing controlled drugs in Taiwan are very difficult to
obtain. This work describes synthetic routes to 5-Meo-DMT-d3, and presents
related characteristic analytical data. To the authors’ knowledge, no report has
addressed these compounds.
Results and discussion
Scheme 1 presents the preparation of the 5-[2H3]-methoxy-N,N-dimethyltryp-
tamine 6. 5-Hydroxy-2-nitrotoluene 1 was treated with CD3I in the presence of
potassium hydroxide and tetrabutylammonium bromide,9–11 to give 4-[2H3]-
methoxy-2-methyl-1-nitro-benzene 2 in 81% yield. As in the Batcho-
Leimgruber synthesis of indole,12–17 compound 2 was condensed with
N,N-dimethylformamide dimethyl acetal to yield [2-(5-[2H3]-methoxy-2-
nitro-phenyl)-vinyl]-dimethyl-amine 3. Reductive cyclization of compound
3 with hydrogen (50 psi) and Pd/C (10%) gave 5-[2H3]-methoxy-1H-indole 4 in
70% yield. A reaction between oxalyl chloride and dimethyl amine formed
2-(5-[2H3]-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxo-acetamide 5 in 55%
yield. The reduction of compound 5 with lithium aluminum hydride produced
5-[2H3]-methoxy-N,N-dimethyltryptamine 6 in 97% yield.
OH
OCD3
OCD3
CD3I
KOH
(CH3)2NCH(OCH3)3
CH3
CH3
N(CH3)2
NO2
NO2
NO2
1
2
3
O
N(CH3)2
1. (COCl)2
2. (CH3)2NH
D3CO
D3CO
H2, Pd
O
N
H
N
H
4
5
N(CH3)2
D3CO
LiAlH4
N
H
6
Scheme 1.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 897–902
DOI: 10.1002/jlcr

SYNTHESIS OF 5-METHOXY-N,N-DIMETHYLTRYPTAMINE
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Experimental
General
1H NMR spectra were obtained at 300 or 500 MHz (indicated in each case),
and 13C NMR spectra were obtained at 75.5 MHz using a Bruker NMR
spectrometer. Chemical shifts (d) are reported in ppm relative to CHCl3 (7.26
and 77.0 ppm). Mass spectra (MS) were obtained using a Micromass Platform
II mass spectrometer at 70 eV. High-resolution mass spectra (HRMS) were
obtained using a Finnigan/Thermo Quest MAT 95XL mass spectrometer.
Infrared spectra were recorded using an ATI Mattson spectrometer. All
reactions were performed in anhydrous solvents. Tetrahydrofuran and diethyl
ether were distilled from sodium-benzophenone in argon. Benzene and N,N-
dimethylformamide were distilled from calcium hydride. All air-sensitive
reactions were performed in dry glassware under nitrogen using a standard
glovebox. Flash column chromatography was performed using MN silica gel
60 (70–230 mesh) which was purchased from Macherey-Nagel.
The following reactions were performed without deuterium-labeled compounds
as starting materials to elucidate the reaction conditions.
Synthesis of 4-[2H3]-methoxy-2-methyl-1-nitro-benzene (2): Adequate
amounts of potassium hydroxide in pellet form (2.53 g, 45.0 mmol)
were ground to powder; tetrbutylammonium bromide (207 mg, 0.6 mmol)
and 5-hydroxy-2-nitrotoluene 1 (6.30 g, 41.0 mmol) were then added,
and blended in a nitrogen atmosphere. CD3I (2.70 ml, 42.5 mmol) was
then added and the mixture was heated in an oil bath for 3 days at 40–458C.
The crude mixture was then transferred to a separating funnel with water,
and extracted using dichloromethane. The extract was dried over an-
hydrous magnesium sulfate. Filtration and concentration yielded a residue,
which was purified by flash column chromatography using silica gel as the
stationary phase and ethyl acetate–hexane (1:19) as the mobile phase, to
1
generate compound 2 (6.14 g, 36.0 mmol). Yield: 81%. m.p.: 54–558C. H
NMR (300 MHz, CDCl3, d): 8.10 (d, J ¼ 8:8 Hz, 1H), 6.81-6.76 (m, 2H), 2.63
(s, 3H). 13C NMR (75 MHz, CDCl3, d): 163.0, 142.1, 137.1, 127.5, 117.4,
111.8, 21.7. IR (KBr, thin film): 3120, 3054, 2985, 2931, 2075, 1608, 1581,
1496, 1334, 1292, 1265 cmꢀ1. MS-FAB (m/z): 170 (M+, 6), 167 (10), 75 (100).
HRMS-FAB (m/z): [M+] calculated for C8H6D3NO3, 170.0767; found
170.0765.
Synthesis of [2-(5-[2H3]-methoxy-2-nitro-phenyl)-vinyl]-dimethyl-amine
(3): A solution of 5-[2H3]-methoxy-2-nitrotoluene 2 (6.07 g, 35.7 mmol) in
N,N-dimethylforamide dimethyl acetal (14.2 ml, 107.1 mmol) and N,N-
dimethylforamide (36.0 ml) was heated at 1308C using a reflux condenser for
7 h.12–17 The condenser was replaced with a distillation apparatus to remove
the remaining N,N-dimethylforamide and N,N-dimethylforamide dimethyl
Copyright # 2006 John Wiley & Sons, Ltd.
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900
Y.-Z. XU AND C. CHEN
acetal. The dark brown residue was used in the subsequent reaction without
further purification.
Synthesis of 5-[2H3]-methoxy-1H-indole (4): A solution of crude compound
3 in benzene (125 ml) and 10% Pd/C (0.80 g) was hydrogenated in an
atmosphere of hydrogen (50 psi) at room temperature using a Parr apparatus.
After being shaken for 1.5 h, the catalyst was removed by filtration through a
bed of celite, and thoroughly extracted using benzene. Concentration left a
residue, which was purified by flash column chromatography using silica gel as
the stationary phase and ethyl acetate-hexane (1:19) as the mobile phase, to
1
produce compound 4 (3.75 g, 25.0 mmol). Yield: 70%. m.p.: 58–598C. H
NMR (300 MHz, CDCl3, d): 8.04 (br, 1H), 7.30 (d, J ¼ 8:6 Hz, 1H), 7.19
(t, J ¼ 2:8 Hz, 1H), 7.11 (d, J ¼ 2:4 Hz, 1H), 6.88 (dd, J ¼ 8:8, 2.4 Hz, 1H),
6.49-6.48 (m, 1H). 13C NMR (75 MHz, CDCl3, d): 154.2, 131.0, 128.5, 125.0,
112.3, 111.8, 102.3, 55.9-54.8 (m). IR (KBr, thin film): 3401, 3100, 2221, 2063,
1612, 1577, 1477, 1322, 1284, 1230, 1164 cmꢀ1. MS-FAB (m/z): 151 (M++1,
100), 150 (74), 132 (35), 117 (9), 116 (3). HRMS-FAB (m/z): [M+] calculated
for C9H6D3NO, 150.0869; found 150.0865.
Synthesis of 2-(5-[2H3]-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxo-aceta-
mide (5): To a cooled and well-stirred solution of oxalyl chloride (2.28 ml,
26.1 mmol) in anhydrous diethyl ether (35 ml) was added 5-methoxyindole-d3
(1.95 g, 13.0 mmol) in portions. Stirring was continued for an additional
30 min, and the red solids thus formed were washed lightly with diethyl ether.
To a solution of dimethylamine hydrochloride (45.8 g, 561.6 mmol) and
sodium hydroxide (22.4 g, 560 mmol) in water (54 ml) was added compound 4
in a little anhydrous diethyl ether. Stirring was continued for a further 30 min,
and the red solid was collected and washed with diethyl ether. The red solid
was dissolved in hot tetrahydrofuran. It was then cooled to room temperature
and diethyl ether was added to precipitate a white solid, 2-(5-[2H3]-methoxy-
1H-indol-3-yl)-N,N-dimethyl-2-oxo-acetamide 5 (1.76 g, 7.1 mmol). Yield:
55%. m.p.: 226–2278C. 1H NMR (300 MHz, CDCl3/CD3OD, d): 7.68
(d, J ¼ 3:3 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J ¼ 8:9 Hz, 1H), 6.78-6.74 (dd,
J ¼ 8:8, 2.5 Hz, 1H), 2.96 (s, 3H), 2.90 (s, 3H). 13C NMR (75 MHz, CDCl3/
CD3OD, d): 186.0, 168.2, 156.4, 136.5, 131.8, 126.0, 114.1, 113.5, 112.8, 103.0,
37.3, 34.0. IR (KBr, thin film): 3131, 3100, 3046, 2896, 2248, 2217, 2071, 1631,
1469, 1442, 1276 cmꢀ1. MS-FAB (m/z): 250 (M++1, 34), 207 (42), 149 (37), 75
(100). HRMS-FAB (m/z): [M++H] calculated for C13H12D3N2O3, 250.1267;
found 250.1272.
Synthesis of [2-(5-[2H3]-methoxy-1H-indol-3-yl)-ethyl]-dimethyl-amine
(6): To a well-stirred suspension of lithium aluminum hydride (0.89 g,
2.3 mmol) in anhydrous tetrahydrofuran (30 ml) was added, in small portions,
a suspension of 2-(5-[2H3]-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxo-acet-
amide 5 (1.46 g, 5.9 mmol) in tetrahydrofuran (20 ml); the mixture was refluxed
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 897–902
DOI: 10.1002/jlcr

SYNTHESIS OF 5-METHOXY-N,N-DIMETHYLTRYPTAMINE
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for 1.5 h. Following cooling in an external ice bath, the reaction complex and
excess hydride were decomposed by the cautious addition of 2 M aqueous
NaOH. The inorganic solid was removed by filtration; the filter cake was
washed using additional diethyl ether. The filtrate and washes were combined
and dried over anhydrous magnesium sulfate, and the solvents were removed
in vacuo, yielding 5-[2H3]-methoxy-N,N-dimethyltryptamine
6 (1.26 g,
1
5.7 mmol). Yield: 97%. H NMR(300 MHz, CDCl3, d): 7.94 (br, 1H), 7.25
(d, J ¼ 8:8 Hz, 1H), 7.04 (d, J ¼ 2:4 Hz, 1H), 7.01 (d, J ¼ 2:3 Hz, 1H), 6.86
(dd, J ¼ 8:8, 2.4 Hz, 1H), 2.93 (t, J ¼ 2:7 Hz, 2H), 2.65 (t, J ¼ 2:3 Hz, 2H),
2.34 (s, 6H). 13C NMR (75 MHz, CDCl3, d): 153.8, 131.5, 127.8, 122.4, 113.9,
112.0, 111.9, 100.6, 60.2, 45.4, 23.8. IR (KBr, thin film): 3131, 3104, 3035,
2946, 2857, 2819, 2784, 2240, 2210, 2059, 1473 cmꢀ1. MS-FAB (m/z): 222
(M++1, 100), 220 (18), 177 (64), 132 (19), 130 (8), 75 (4). HRMS-FAB (m/z):
[M++H] calculated for C13H16D3N2O, 222.1682; found 222.1687.
Acknowledgements
The authors thank Ms L. M. Hsu, at the Instruments Center, National Chung
Hsing University, Ms S. C. Lin, Ms H. C. Tan, and Ms F. L. Liao, at the
Instrument Center, National Tsing Hwa University for their help in obtaining
HRMS, and 13C NMR spectra, and in performing X-ray crystallography. We
would also like to thank the National Bureau of Controlled Drugs,
Department of Health, Taiwan, Republic of China, for financially supporting
this work under Contract DOH94-NNB-1007.
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Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 897–902
DOI: 10.1002/jlcr