SYNTHESIS OF DEUTERIUM-LABELLED STANDARDS 663
sulfate. After filtration and concentration, the resulting
residue was dissolved in dry diethyl ether, and
saturated with hydrogen chloride. The formed cry-
stals of (7)-2-(2,5-[2H6]-dimethoxy-4-methyl-phenyl)-
1-methyl-ethylamine (5) were removed by filtration,
washed with anhydrous diethyl ether. The hydrochloric
acid salt of 5 was crystallized from methanol/diethyl
ether, yielding 5.HCl (3.03 g, 12.06 mmol). Yield: 75%.
M.p.: 200–2018C. 1H NMR (300 MHz, CDCl3, d): 8.35
(s, br, 2H), 6.67 (s, 2H), 3.71–3.67 (m, 1H), 3.10 (dd,
J ¼ 1:33, 5.9 Hz, 1H), 2.86 (dd, J ¼ 13:3, 9.4 Hz, 1H), 2.19
(s, 3H), 1.36 (d, J ¼ 6:5 Hz, 3 H). 13C NMR (75MHz, CDCl3,
d): 151.4, 151.2, 126.3, 121.7, 114.0, 113.7, 5.9–54.4
(m), 48.3, 36.5, 18.3, 16.3. IR (KBr, thin film): 2940,
2736, 2694, 2595, 2507, 2218, 2068, 1994, 1589,
1507, 1408, 1229, 1108, 1014, 968, 674 cmꢀ1. MS-EI
(m/z): 215 (Mþ–HCl, 4), 172 (100), 154 (28), 139 (8), 125
(4), 107 (5), 92 (7), 79 (7), 77 (6), 65 (3). HRMS-EI (m/z):
[Mþ] calcd for C12H13D6NO2, 215.1786; found 215.1794.
sulfate, and then the solvent was removed under
vacuum. The resulting residue was purified by flash
column chromatography using silica gel as the statio-
nary phase and ethyl acetate–hexane (1:3) as the
mobile phase, producing 3-bromo-4,5-methylene-
dioxybenzaldehyde 8 (0.73 g, 3.2 mmol) as a white
crystalline. Yield: 63%. M.p.: 124–124.58C. 1H NMR
(300 MHz, CDCl3, d): 9.77 (s, 1H), 7.54 (s, 1H), 7.28
(s, 1H), 6.10 (s, 2H). 13C NMR (75 MHz, CDCl3 d):
189.0, 151.2, 148.9, 132.8, 130.9, 106.2, 102.5,
100.9. IR (KBr, thin film): 2853, 1686, 1594, 1430,
1270, 1036, 927, 849, 815, 575 cmꢀ1. MS-EI (m/z):
230 (97), 229 (99), 228 (Mþ, 100), 227 (Mþ–1, 94), 199
(24), 63 (29), 62 (32). HRMS-EI (m/z): [Mþ] calcd for
C8H5BrO3, 227.9422; found 227.9429.
Synthesis of 3-hydroxyl-4,5-methyenedioxybenzalde-
hyde (11). A mixture of 3-bromo-4,5-methylenediox-
ybenzaldehyde 8 (1.30 g, 5.7 mmol), cyclohexylamine
(2.2 ml, 19 mmol) and toluene (10 ml) was refluxed in a
Dean–Stark apparatus for 3.5 h. After cooling, the
excess solvent was removed using a rotary evaporator,
and thoroughly dried in vacuum, producing 3-bromo-
Synthesis of 3-bromo-4,5-dihydroxy-benzaldehyde (7).
A solution of commercial 3,4-dihydroxybenzaldehyde 6
(1.80g, 13.0mmol) in warm acetic acid (20 ml) was
filtered until free of any insoluble solid, yielding a clear
solution. Elemental bromine (0.80ml, 15.6 mmol) was
added with vigorous stirring. The reaction became
spontaneously hotter, to around 308C, and solids
appeared after about 5 min of stirring, which was
continued for 1.5 h. Then, the light gray solids that
had formed were removed by filtration and lightly
washed using acetic acid. These were dried in vacuum
until free from acetic acid. The product was purified by
recrystallization using 50% ethanol, producing the
product, 3-bromo-4,5-dihydroxybenzaldehyde 7 (1.50 g,
6.9 mmol). Yield: 53%. M.p.: 221–2228C. 1H NMR
(300MHz, CD3OD, d): 9.65 (s, 1H), 7.52 (d, J ¼ 3:5 Hz,
1 H), 7.23 (d, J ¼ 3:5 Hz, 1 H). 13C NMR (75 MHz, CD3OD
d): 190.4, 149.7, 146.3, 129.5, 127.5, 112.5, 109.1. IR
(KBr, thin film): 3423, 1652, 1579, 1442, 1309, 1255,
1186, 862, 580 cmꢀ1. MS-EI (m/z): 218 (68), 217 (100),
216 (Mþ, 70), 215 (Mþ–1, 95), 187 (16), 107 (16), 79 (16),
51 (27). HRMS-EI (m/z): [Mþ] calcd for C7H5BrO3,
215.9422; found 215. 9418.
4,5-methylenedioxybenzylidine-N-cyclohexylamine
9
(1.50 g, 4.8 mmol) in a yield of 86%. A solution of
compound 9 (3.49 g, 11.3 mmol) in anhydrous diethyl
ether (80 ml) was placed in an atmosphere of argon,
stirred magnetically, and cooled to ꢀ788C; a white
fine crystalline appeared. n-Butyllithium (16.54 ml,
13.5 mmol, 0.82 M in hexane) was added, and the fine
solids were dissolved; then tributyl borate (6.3 ml,
24 mmol) was added. After the system had returned
to room temperature, the reaction was quenched with
saturated aqueous ammonium sulfate (32 ml). The
organic layer was separated, washed with additional
ammonium sulfate solution, and stripped off volatiles
in vacuum. The residual oil was dissolved in 50%
methanol/water (158 ml), and treated with hydrogen
peroxide (3.2 ml, 30%). After it had been swirled for
15 min, the reaction was quenched using a solution of
ammonium sulfate (16 g) in water (79 ml). This aqueous
phase (pH about 8) was extracted with dichloro-
methane. The extracts were pooled and the solvent
removed under vacuum. The residual oil was treated
with dilute HCl and heated at 1008C. After all the
residue had dissolved, the solution was cooled to room
temperature and extracted with 5% NaOH. Acidifica-
tion of the pooled aqueous fractions with HCl, followed
by extraction with dichloromethane and evaporation
of the solvent, yielded a residue which was purified
by flash column chromatography using silica gel as
the stationary phase and ethyl acetate–hexane (1:3) as
the mobile phase, producing white crystals of
3-hydroxyl-4,5-methyenedioxybenzaldehyde 11 (0.91g,
Synthesis of 3-bromo-4,5-methylenedioxybenzalde-
hyde (8). To a solution of 3-bromo-4,5-dihydroxyben-
zaldehyde 7 (1.10 g, 5.1 mmol) in DMSO (3.6 ml) was
added methylene iodide (0.87 ml, 10.8 mmol) followed
by anhydrous potassium carbonate (2.00 g), which
was heated at 1008C for 3 h. After it had returned to
room temperature, it was added to water (100 ml),
made strongly basic by the addition of sodium
hydroxide, and extracted using dichloromethane.
These extracts were dried over anhydrous sodium
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 660–665
DOI: 10.1002.jlcr