JLCR

Journal of Labelled Compounds and Radiopharmaceuticals

J Label Compd Radiopharm 2007; 50: 660–665.
Published online 4 June 2007 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1378

Research Article

Synthesis of deuterium-labelled standards of (7)-DOM and

(7)-MMDA
AJAM C. SHAIKH, YU-YUN WANG and CHINPIAO CHEN*
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, Republic of China

Received 7 March 2007; Revised 22 March 2007; Accepted 29 March 2007

Abstract: This study describes the synthesis of deuterium-labelled (7)-4-methyl-2,5-dimethoxyamphetamine (DOM)

and (7)-1-(7-methoxy-1,3-benzodioxol-5-yl)propan-2-amine (MMDA). The isotopically labelled compounds are
potentially used as internal standards in gas chromatography–mass spectrometry (GC–MS) assays. Copyright #
2007 John Wiley & Sons, Ltd.

Keywords: DOM; MMDA; deuterium labelled; internal standard

Introduction control drugs as internal standards for GC–MS analy-

sis.4–6 This work describes synthetic routes to DOM-d6
Unknown drugs of abuse are generally detected and MMDA-d3, and presents relevant characteristic
and identified by gas chromatography–mass spectro- analytical data. The compounds investigated in this
metry (GC–MS) owing to the high sensitivity of this study have not been examined before.
method and its ability to separate complex mixtures of
organic compounds. 4-Methyl-2,5-dimethoxyampheta- Results and discussion
mine (DOM)1 is a psychedelic hallucinogenic drug of
the phenethylamine class, and is occasionally used as Although DOM7–14 and MMDA15 have been readily
an entheogen. In the United States, DOM is classified prepared by several synthetic routes, preparing (7)-
as a Schedule 1 substance, and is similarly controlled [2H6]-DOM and (7)-[2H3]-MMDA have not been de-
in other parts of the world. scribed. Scheme 1 presents the general scheme for
1-(7-Methoxy-1,3-benzodioxol-5-yl)propan-2-amine preparing (7)-[2H6]-DOM (5). 1,4-[2H6]-Dimethoxy-2-
(MMDA) is a biologically active derivative of phenethy- methyl-benzene (2) was prepared by reacting 2-methyl-
lamine and amphetamine. Its analogs include 3,4- benzene-1,4-diol with [2H3]-methyl iodide.4–6,16–18
methylenedioxyamphetamine (MDA), lophophine and Compound 2 was treated with dichloromethyl methyl
3,4-methylenedioxy-n-methylamphetamine (MDMA), ether and TiCl4 to yield 2,5-[2H6]-dimethoxy-4-methyl-
and it resembles the psychopharmacologically active benzaldehyde (3),19–24 which was then condensed with
essential oils elemicin and myristicin, which are found nitroethane to yield 1,4-[2H6]-dimethoxy-2-methyl-
in nutmeg. 5-(2-nitro-propenyl)-benzene (4). The reduction of this
The abuse of psychoactive phenylethylamines and compound 4 with LiAlH4 produced (7)-2-(2,5-[2H6]-
phenylisopropylamines has become a very serious dimethoxy-4-methyl-phenyl)-1-methyl-ethylamine (5).
social problem in Taiwan in the last decade.2,3 Stan- Scheme 2 is the general synthesis of (7)-[2H3]-MMDA
dard samples for analyzing controlled drugs in Taiwan (14).15 Bromination of commercially available proto-
are very difficult to obtain. Many researchers are catechualdehyde 6 in acetic acid gave 3-bromo-proto-
interested in the preparation of deuterium-labelled catechualdehyde 7. Treatment of 7 with diiodomethane
under mildly basic conditions gave dioxymethylated
aldehyde 8. The compound 8 was treated with cyclo-
*Correspondence to: Chinpiao Chen, Department of Chemistry, hexylamine in Dean–Stark using toluene as a solvent to
National Dong Hwa University, Soufeng, Hualien 974, Taiwan, Republic form a cyclohexylamine adduct 9. Treating 9 with
of China. E-mail: [email protected]
Contract/grant sponsor: National Bureau of Controlled Drugs; con- n-butyllithium caused it to undergo rapid lithium–
tract/grant number: DOH95-NNB-1001 halogen exchange to form the corresponding lithio

Copyright # 2007 John Wiley & Sons, Ltd.

 SYNTHESIS OF DEUTERIUM-LABELLED STANDARDS 661

HO D3CO D3CO CHO

CD3I Cl2CHOCH3

KOH TiCl4
Me OH Me OCD3 Me OCD3

1 2 3

D3CO NO2 D3CO NH2

CH3CH2NO2 LAH
NH4OAc CH3
Me Me OCD3
OCD3
4 5
Scheme 1

HO CHO O CHO
HO CHO Br2 NH2
CH2I2

HO K2CO3 O
HO
Br Br
6 7 8

1. H2O2 O CHO
O n-BuLi O N
N
2. conc HCl
B(OBu)3 O
O O
100°C
Br B(OBu)2 OH
9 10 11

O CHO O NO2 O NH2

CD3I CH3CH2NO2
LAH
K2CO3 O NH4OAc O Me Me
O
OCD3 OCD3 OCD3
12 13 14
Scheme 2

derivative, which upon reaction with tributyl borate this compound 14 was treated with HCl gas to form
formed 10 by conversion of the lithio derivative to (7)-3-methoxy-4,5-methylenedioxyamphetamine hy-
organoborane. The oxidation of the C–B bond with drochloride (MMDA).
basic hydrogen peroxide, and finally, the hydrolysis of
the protected Schiff’s base produced 3-hydroxy-4,5- Experimental
methylenedioxybenzaldehyde 11 in good yield. Hydro-
xybenzaldehyde 11 was alkylated by treating it with General
[2H3]-methyl iodide in the presence of K2CO3 to give
1
myristicinaldehyde 12 in a 80–95% yield. Next, the H NMR spectra were acquired at 300 MHz (indicated in
corresponding myristicinaldehyde 12 was treated with each case), and 13C NMR were acquired at 75.5 MHz on
nitroethane to give 13, which was reduced using a Bruker NMR spectrometer. Chemical shifts (d) are
lithium aluminum hydride. Attempts to purify obtained reported in ppm relative to CHCl3 (7.26 and 77.0 ppm).
amine 14 by column chromatography failed; so firstly, Mass spectra (MS) and high-resolution mass spectra
amine was treated with picric acid to give picrate salt, (HRMS) were determined on a Finnigan/Thermo Quest
which on recrystallization gave the pure picrate salt of MAT 95XL mass spectrometer. Infrared spectra were
amine. Subsequent treatment of this picrate salt with recorded using a JASCO FT/IR 410 spectrometer. All
NaOH and extraction gave pure compound 14. To reactions were performed in anhydrous solvents.
convert this amine to the corresponding hydrochloride, Tetrahydrofuran and diethyl ether were distilled from

Copyright # 2007 John Wiley & Sons, Ltd. J Label Compd Radiopharm 2007; 50: 660–665
DOI: 10.1002.jlcr
662 A. C. SHAIKH ET AL.

sodium–benzophenone in argon. Benzene and N,N- phase to give 3 as a white crystalline (5.14 g,
dimethylformamide were distilled from calcium hy- 27.6 mmol). Yield: 87%. M.p.: 74–758C. 1H NMR
dride. All air-sensitive reactions were performed in dry (300 MHz, CDCl3, d): 10.40 (s, 1H), 7.25 (s, 1H), 6.80
glassware under nitrogen using a standard glovebox. (s, 1H), 2.28 (s, 3H). 13C NMR (75 MHz, CDCl3, d):
Flash column chromatography was performed using 189.1, 156.5, 151.8, 136.5, 122.7, 114.6, 107.4, 55.5–
MN silica gel 60 (70–230 mesh) or basic Al2O3 which 54.8 (m), 17.2. IR (KBr, thin film): 3056, 2868, 2776,
were purchased from Macherey-Nagel. 2213, 2069, 1658, 1612, 1497, 1416, 1280, 1223,
All reactions were initially optimized using unlabelled 1111, 1006, 889, 664, 626 cm
1. MS-EI (m/z): 186
compounds. (Mþ , 100), 168 (80), 157 (7), 151 (7), 140 (56), 123 (22),
112 (27), 93 (15), 77 (12), 66 (12), 53 (11). HRMS-EI
Synthesis of 1,4-[2H6]-dimethoxy-2-methyl-benzene (2). (m/z): [Mþ ] calcd for C10H6D6O3, 186.1157; found
Potassium hydroxide pellets (4.81 g, 85.8 mmol) were 186.1165.
round to a powder; tetrabutylammonium bromide
(4.14 g, 33.4 mmol) and methylhydroquinone (4.14 g, Synthesis of 1,4-[2H6]-dimethoxy-2-methyl-5-(2-nitro-pro-
33.4 mmol) were added, and the whole ground together penyl)-benzene (4). A solution of 2,5-[2H6]-dimethoxy-
in a nitrogen atmosphere at room temperature.16–19 4-methyl-benzaldehyde (3) (5.00 g, 26.9 mmol) in glacial
[2H3]-Methyl iodide (15.0 g, 6.44 ml, 103.5 mmol; iso- acetic acid (23.1 ml) was treated with nitroethane
topic abundance 99.5%, Cambridge Isotope Labora- (3.11 ml, 43.3 mmol) and anhydrous ammonium acetate
tories Inc.) was then added and the mixture was heated (2.10 g, 26.9 mmol). This mixture was heated at 1008C
in an oil bath for four days at 558C. The crude mixture for 5 h and the excess reagent and solvent were removed
was then transferred to a separating funnel with water under vacuum. The residue was suspended in water
and dichloromethane, and the aqueous phase was and extracted with dichloromethane. The extracts were
extracted using dichloromethane. The extracts were dried over anhydrous magnesium sulfate. Following
dried over anhydrous magnesium sulfate. Filtration filtration and concentration, the resulting residue was
and concentration yielded a residue that was purified purified by flash column chromatography using silica
by flash column chromatography using silica gel as the gel as the stationary phase and using ethyl acetate–
stationary phase and ethyl acetate–hexane (1:19) as the hexane (1:39) as the mobile phase, producing com-
mobile phase, producing (2) as a yellowish liquid (5.10 g, pound 4 (4.10 g, 16.9 mmol). Yield: 63%. M.p.: 90–918C.
32.2 mmol). Yield: 96%. 1H NMR (300 MHz, CDCl3, d): 1
H NMR (300 MHz, CDCl3, d): 8.29 (s, 1H), 6.76 (s, 1H),
6.76–6.66 (m, 3H), 2.21 (s, 3H). 13C NMR (75 MHz, 6.75 (s, 1H), 2.42 (s, 3H), 2.27 (s, 3H). 13C NMR (75 MHz,
CDCl3, d): 157.0, 155.6, 131.2, 120.6, 114.2, 114.2, CDCl3, d): 152.4, 151.4, 146.7, 131.1, 130.0, 118.7,
58.5–57.7 (m), 19.9. IR (KBr, thin film): 3038, 2951, 114.0, 111.5, 55.5–54.8 (m), 16.7, 14.3. IR (KBr, thin
2923, 2213, 2067, 1499, 1231, 1112, 996, 865, 796, film): 2924, 2845, 2214, 2072, 1649, 1506, 1310, 1227,
687 cm
1. MS-EI (m/z): 158 (Mþ , 91), 140 (100), 112 1105, 1004, 969, 866, 656 cm
1. MS-EI (m/z): 243 (Mþ ,
(20), 94 (18), 77 (19), 66 (17), 51 (4). HRMS-EI (m/z): 100), 209 (4), 196 (28), 178 (32), 161 (24), 150 (3), 140
[Mþ ] calcd for C9H6D6O2, 158.1208; found 158.1221. (4), 132 (4), 115 (4), 103 (4), 93 (3), 77 (5), 65 (4). HRMS-
EI (m/z): [Mþ ] calcd for C12H9D6NO4, 243.1372; found
Synthesis of 2,5-[2H6]-dimethoxy-4-methyl-benzalde- 243.1369.
hyde (3). To a solution of 2 (5.00 g, 31.6 mmol) in dry
dichloromethane (600 ml) that was cooled in an ice Synthesis of (7)-2-(2,5-[2H6]-dimethoxy-4-methyl-phe-
bath was added titanium chloride (6.38 ml, 58.2 mmol) nyl)-1-methyl-ethylamine (5). A solution of 1,4-[2H6]-
and dichloromethyl methyl ether (C12CHOCH3) (5.3 ml, dimethoxy-2-methyl-5-(2-nitro-propenyl)-benzene (4)
58.8 mmol) in an argon atmosphere.19–24 The dark red (3.90 g, 16.0 mmol) in anhydrous diethyl ether
reaction solution was stirred at room temperature for (105 ml) was slowly added to a well-stirred suspension
15 min until all of the starting material was completely mixture of lithium aluminum hydride (2.44 g,
consumed, as monitored by thin layer chromatography 64.2 mmol) in anhydrous diethyl ether (22 ml). The
(TLC). The reaction was quenched by adding water mixture was then brought up to a reflux, which was
(230 ml), and the dichloromethane layer was washed maintained for 20 h, and then cooled with an external
with water (170 ml) and then dried over anhydrous ice bath; the excess hydride was destroyed by the
magnesium sulfate. The solution was filtered, and the cautious addition of water. The quenched mixture was
filtrate was concentrated by rotary vacuum evapora- filtered through celite, and washed with tetrahydrofur-
tion. The residue was purified by flash column an, and the filtrate was concentrated. The aqueous
chromatography using silica gel as the stationary phase was extracted using dichloromethane. The
phase and ethyl acetate–hexane (1:19) as the mobile organic phase was dried over anhydrous sodium

Copyright # 2007 John Wiley & Sons, Ltd. J Label Compd Radiopharm 2007; 50: 660–665
DOI: 10.1002.jlcr
 SYNTHESIS OF DEUTERIUM-LABELLED STANDARDS 663

sulfate. After filtration and concentration, the resulting sulfate, and then the solvent was removed under
residue was dissolved in dry diethyl ether, and vacuum. The resulting residue was purified by flash
saturated with hydrogen chloride. The formed cry- column chromatography using silica gel as the statio-
stals of (7)-2-(2,5-[2H6]-dimethoxy-4-methyl-phenyl)- nary phase and ethyl acetate–hexane (1:3) as the
1-methyl-ethylamine (5) were removed by filtration, mobile phase, producing 3-bromo-4,5-methylene-
washed with anhydrous diethyl ether. The hydrochloric dioxybenzaldehyde 8 (0.73 g, 3.2 mmol) as a white
acid salt of 5 was crystallized from methanol/diethyl crystalline. Yield: 63%. M.p.: 124–124.58C. 1H NMR
ether, yielding 5.HCl (3.03 g, 12.06 mmol). Yield: 75%. (300 MHz, CDCl3, d): 9.77 (s, 1H), 7.54 (s, 1H), 7.28
M.p.: 200–2018C. 1H NMR (300 MHz, CDCl3, d): 8.35 (s, 1H), 6.10 (s, 2H). 13C NMR (75 MHz, CDCl3 d):
(s, br, 2H), 6.67 (s, 2H), 3.71–3.67 (m, 1H), 3.10 (dd, 189.0, 151.2, 148.9, 132.8, 130.9, 106.2, 102.5,
J ¼ 1:33, 5.9 Hz, 1H), 2.86 (dd, J ¼ 13:3, 9.4 Hz, 1H), 2.19 100.9. IR (KBr, thin film): 2853, 1686, 1594, 1430,
(s, 3H), 1.36 (d, J ¼ 6:5 Hz, 3 H). 13C NMR (75 MHz, CDCl3, 1270, 1036, 927, 849, 815, 575 cm
1. MS-EI (m/z):
d): 151.4, 151.2, 126.3, 121.7, 114.0, 113.7, 5.9–54.4 230 (97), 229 (99), 228 (Mþ , 100), 227 (Mþ –1, 94), 199
(m), 48.3, 36.5, 18.3, 16.3. IR (KBr, thin film): 2940, (24), 63 (29), 62 (32). HRMS-EI (m/z): [Mþ ] calcd for
2736, 2694, 2595, 2507, 2218, 2068, 1994, 1589, C8H5BrO3, 227.9422; found 227.9429.
1507, 1408, 1229, 1108, 1014, 968, 674 cm
1. MS-EI
(m/z): 215 (Mþ –HCl, 4), 172 (100), 154 (28), 139 (8), 125 Synthesis of 3-hydroxyl-4,5-methyenedioxybenzalde-
(4), 107 (5), 92 (7), 79 (7), 77 (6), 65 (3). HRMS-EI (m/z): hyde (11). A mixture of 3-bromo-4,5-methylenediox-
[Mþ ] calcd for C12H13D6NO2, 215.1786; found 215.1794. ybenzaldehyde 8 (1.30 g, 5.7 mmol), cyclohexylamine
(2.2 ml, 19 mmol) and toluene (10 ml) was refluxed in a
Synthesis of 3-bromo-4,5-dihydroxy-benzaldehyde (7). Dean–Stark apparatus for 3.5 h. After cooling, the
A solution of commercial 3,4-dihydroxybenzaldehyde 6 excess solvent was removed using a rotary evaporator,
(1.80 g, 13.0 mmol) in warm acetic acid (20 ml) was and thoroughly dried in vacuum, producing 3-bromo-
filtered until free of any insoluble solid, yielding a clear 4,5-methylenedioxybenzylidine-N-cyclohexylamine 9
solution. Elemental bromine (0.80 ml, 15.6 mmol) was (1.50 g, 4.8 mmol) in a yield of 86%. A solution of
added with vigorous stirring. The reaction became compound 9 (3.49 g, 11.3 mmol) in anhydrous diethyl
spontaneously hotter, to around 308C, and solids ether (80 ml) was placed in an atmosphere of argon,
appeared after about 5 min of stirring, which was stirred magnetically, and cooled to
788C; a white
continued for 1.5 h. Then, the light gray solids that fine crystalline appeared. n-Butyllithium (16.54 ml,
had formed were removed by filtration and lightly 13.5 mmol, 0.82 M in hexane) was added, and the fine
washed using acetic acid. These were dried in vacuum solids were dissolved; then tributyl borate (6.3 ml,
until free from acetic acid. The product was purified by 24 mmol) was added. After the system had returned
recrystallization using 50% ethanol, producing the to room temperature, the reaction was quenched with
product, 3-bromo-4,5-dihydroxybenzaldehyde 7 (1.50 g, saturated aqueous ammonium sulfate (32 ml). The
6.9 mmol). Yield: 53%. M.p.: 221–2228C. 1H NMR organic layer was separated, washed with additional
(300 MHz, CD3OD, d): 9.65 (s, 1H), 7.52 (d, J ¼ 3:5 Hz, ammonium sulfate solution, and stripped off volatiles
1 H), 7.23 (d, J ¼ 3:5 Hz, 1 H). 13C NMR (75 MHz, CD3OD in vacuum. The residual oil was dissolved in 50%
d): 190.4, 149.7, 146.3, 129.5, 127.5, 112.5, 109.1. IR methanol/water (158 ml), and treated with hydrogen
(KBr, thin film): 3423, 1652, 1579, 1442, 1309, 1255, peroxide (3.2 ml, 30%). After it had been swirled for
1186, 862, 580 cm
1. MS-EI (m/z): 218 (68), 217 (100), 15 min, the reaction was quenched using a solution of
216 (Mþ , 70), 215 (Mþ –1, 95), 187 (16), 107 (16), 79 (16), ammonium sulfate (16 g) in water (79 ml). This aqueous
51 (27). HRMS-EI (m/z): [Mþ ] calcd for C7H5BrO3, phase (pH about 8) was extracted with dichloro-
215.9422; found 215. 9418. methane. The extracts were pooled and the solvent
removed under vacuum. The residual oil was treated
Synthesis of 3-bromo-4,5-methylenedioxybenzalde- with dilute HCl and heated at 1008C. After all the
hyde (8). To a solution of 3-bromo-4,5-dihydroxyben- residue had dissolved, the solution was cooled to room
zaldehyde 7 (1.10 g, 5.1 mmol) in DMSO (3.6 ml) was temperature and extracted with 5% NaOH. Acidifica-
added methylene iodide (0.87 ml, 10.8 mmol) followed tion of the pooled aqueous fractions with HCl, followed
by anhydrous potassium carbonate (2.00 g), which by extraction with dichloromethane and evaporation
was heated at 1008C for 3 h. After it had returned to of the solvent, yielded a residue which was purified
room temperature, it was added to water (100 ml), by flash column chromatography using silica gel as
made strongly basic by the addition of sodium the stationary phase and ethyl acetate–hexane (1:3) as
hydroxide, and extracted using dichloromethane. the mobile phase, producing white crystals of
These extracts were dried over anhydrous sodium 3-hydroxyl-4,5-methyenedioxybenzaldehyde 11 (0.91 g,

Copyright # 2007 John Wiley & Sons, Ltd. J Label Compd Radiopharm 2007; 50: 660–665
DOI: 10.1002.jlcr
664 A. C. SHAIKH ET AL.

5.5 mmol). Yield: 49%. M.p.: 134–134.58C. 1H (300 MHz, CDCl3 d): 149.3, 146.5, 143.7, 137.1, 133.7, 126.6,
CD3OD, d): 9.61 (s, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 6.04 111.3, 103.7, 102.1, 44.0, 14.2. IR (KBr, thin film):
(s, 2H). 13C NMR (75 MHz, CD3OD, d): 191.0, 149.7, 2916, 2349, 1626, 1521, 1343, 1297, 1157, 854,
141.1, 140.2, 131.8, 115.3, 102.3, 100.2. IR (KBr, thin 617 cm
1. MS-EI (m/z): 240 (Mþ 100), 194 (13), 193
film): 3262, 1633, 1606, 1457, 1336, 1183, 1121, 1091, (79), 136 (41), 118 (23), 90 (20), 89 (29), 63 (15). HRMS-
920, 834, 753 cm
1. MS-EI (m/z): 166 (Mþ , 100), 165 EI (m/z): [Mþ ] calcd for C11H8D3NO5, 240.0822; found
(68), 135 (19), 79 (13), 51 (14). HRMS-EI (m/z): [Mþ ] 240.0820.
calcd for C8H6O4 166.0266; found 166.0263.
Synthesis of (7)-2-(7-[2H3]-methoxy-benzo[1,3]dioxol-
2
Synthesis of 3-[ H3]-methoxy-4,5-methylenedioxyben- 5-yl)-1-methyl-ethylamine (14). A suspension of
zaldehyde (12). A solution of 3-hydroxy-4,5-methyle- lithium aluminum hydride (0.83 g, 22.0 mmol) in anhy-
nedioxybenzaldehyde 11 (1.50 g, 9.0 mmol) in dry drous diethyl ether (50 ml) was magnetically stirred,
acetone (35 ml) was treated with [2H3]-methyl iodide and heated in an inert atmosphere to a gentle reflux.
(1.0 ml, 16.0 mmol) and powdered anhydrous K2CO3 The condensing diethyl ether leached 1-(3-[2H3]-
(1.70 g, 11.9 mmol) and was maintained at reflux for methoxy-4,5-methylenedioxyphenyl)-2-nitropropene 13
5 h. After 1 h of heating, a white suspension appeared. (1.11 g, 4.6 mmol) from a Soxhlet thimble in a shunted
After the reaction had been completed, all volatiles were reflux condenser. Subsequently, compound 13 was
stripped under vacuum. The residue was dissolved in added to the reaction medium as a warm saturated
water; was made strongly basic with NaOH and was diethyl ether solution. When the addition had been
extracted with dichloromethane. The combined ex- completed, the refluxing was maintained for an
tracts were dried over anhydrous sodium sulfate. The additional 2 h. The reaction was then cooled and the
removal of the solvent under vacuum gave a residue, excess hydride was destroyed by adding 1.5 N H2SO4
which was purified by flash column chromatography (45 ml, the first 20 ml a drop at a time and with very good
using silica gel as the stationary phase and ethyl stirring). The phases were separated and then sufficient
acetate–hexane (1:19) as the mobile phase, yielding saturated aqueous Na2CO3 was added to the aqueous
3-[2H3]-methoxy-4,5-methylenedioxybenzaldehyde 12 phase to bring the pH up to about 6. The system was
(1.35 g, 7.4 mmol). Yield: 82%. M.p.: 133.5–134.58C. heated to 808C and filtered through a coarse sintered
1
H NMR (300 MHz, CDCl3 d): 9.70 (s, 1H), 7.13 (d, glass funnel to remove some of the insoluble fines. The
J ¼ 1:2 Hz, 1H), 7.05 (d, J ¼ 1:2 Hz, 1H), 6.10 (s, 2H), clear filtrate was heated almost to boil, and treated with
13
C NMR (75 MHz, CDCl3 d): 190.1, 149.4, 144.0, a solution of 1.10 g of 90% picric acid in 12 ml boiling
140.9, 131.8, 110.3, 103.6, 102.6. IR (KBr, thin film): EtOH. Crystals of the picrate formed immediately at the
2844, 2360, 1697, 1624, 1474, 1232, 1134, 1090, 842, edges, and as the reaction flask was cooled in an ice
736 cm
1. MS-EI (m/z): 183 (Mþ 100), 182 (86), 135 bath, the entire reaction set to a yellow mass of crystals,
(14), 79 (17), 51 (18), 50 (10). HRMS-EI (m/z): [Mþ ] which were removed by filtration, washed sparingly with
calcd for C9H5D3O4, 183.0608; found 183.0614. 80% EtOH, and dried in air to give the picrate salt of
MMDA. This sample was recrystallized using EtOH. The
Synthesis of 1-(3-[2H3]-methoxy-4,5-mehylenedioxyphe- salt was treated with 7 ml 5% NaOH, before the red
nyl)-2-nitropropene (13). A solution of 3-[2H3]-methoxy- solution was decanted from some insolubles. Added
4,5-methylenedioxybenzaldehyde 12 (0.70 g, 3.8 mmol) water and NaOH effectively dissolved everything and the
in glacial acetic acid (2.1 ml) was treated with nitro- resulting basic aqueous phase was extracted with
ethane (0.35 ml, 4.9 mmol) and anhydrous ammonium dichloromethane. The pooled extracts were stripped off
acetate (0.27 g, 3.5 mmol). This was heated at 1008C in vacuum, and the residue dissolved in 30 ml anhy-
for 1.5 h. After the reaction had completed, it was drous Et2O and saturated with anhydrous HCl gas.
treated with water with good stirring until just short of White crystals precipitated strongly, and were removed
turbidity. It was then extracted with dichloromethane. by filtration, washed with Et2O, and air dried to give (7)-
Extracts were dried over anhydrous sodium sulfate and 3-[2H3]-methoxy-4,5-methylenedioxyamphetamine hy-
concentration yielded a residue which was purified by drochloride (MMDA) 14 (0.72 g, 2.9 mmol). Yield: 63%.
flash column chromatography using silica gel as the M.p.: 190.0–191.58C. 1H NMR (300 MHz, CD3OD, d): 6.46
stationary phase and ethyl acetate–hexane (3:97) as the (d, J ¼ 1:5 Hz, 1H), 6.43 (d, J ¼ 1:5 Hz, 1H), 5.9 (s, 2H),
mobile phase, producing light yellow solids of 1-(3-[2H3]- 3.4 (m, 1H), 2.78 (m, 2H), 1.6 (d, J ¼ 6:0 Hz, 3H).
13
methoxy-4,5-mehylenedioxyphenyl)-2-nitropropene 13 C NMR (75 MHz, CD3OD, d): 149.4, 143.8, 134.5,
(0.46 g, 1.9 mmol). Yield: 50%. M.p.: 106–1088C. 1H 130.2, 109.2, 102.7, 101.2, 48.9, 43.4, 40.2, 17.0.
NMR (300 MHz, CDCl3 d): 8.00 (s, 1H), 6.66 (s, 1H), 6.63 IR (KBr thin film): 3457, 2975, 1634, 1514, 1107, 1135.
(s, 1H), 6.05 (s, 2H), 2.46 (s, 3H). 13C NMR (75 MHz, MS-EI (m/z): 212 (Mþ –Cl, 1.5), 169 (100), 168 (41),

Copyright # 2007 John Wiley & Sons, Ltd. J Label Compd Radiopharm 2007; 50: 660–665
DOI: 10.1002.jlcr
 SYNTHESIS OF DEUTERIUM-LABELLED STANDARDS 665

120 (9), 92 (11), 79 (6), 64 (13). HRMS-EI (m/z): [Mþ –Cl] 10. Coutts RT, Malicky JL. Can J Chem 1974; 52:
calcd for C11H12D3NO3, 212.1237; found 212.1237. 395–399.
11. Matin SB, Callery PS, Zweig JS, O’Brien A,
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DOI: 10.1002.jlcr