Monoamine transport inhibition by MDMA analogues
T Montgomery et al
1123
(
3 ꢀ 80 ml) and again the organic phases were discarded. The
adjusted to pH 2 with concentrated HCl, stirred for 1 h and
then extracted with ethyl acetate (3 ꢀ 20 ml) and the organic
phase discarded. The aqueous phase was adjusted to pH 10
with the addition of NaOH and saturated with sodium
chloride. The solution was again extracted with ethyl acetate
(3 ꢀ 20 ml), the organic fractions were combined, dried over
sodium sulphate and concentrated in vacuo. The oil was
dissolved in ethanol (5 ml) and precipitation of the product
occurred after adding a few drops of concentrated HCl
aqueous layer was basified with 30% NaOH and then
extracted with dichloromethane (3 ꢀ 80 ml), the organic
fractions were combined, dried over magnesium sulphate
and concentrated in vacuo. The oil was dissolved in
isopropanol (5 ml) and precipitation of the product occurred
after adding a few drops of concentrated hydrochloric acid
followed by diethyl ether addition. Filtration and drying
afforded the required compounds as white/grey solids.
followed by diethyl ether addition. Filtration and drying
1
1
2
,3-MDMA. (45% yield) H NMR (300 MHz, DMSO-d
6
): d
afforded HMMA.HCl as a white powder (0.62 g, 24%):
H
3
3
1
3
1
.08 (d, H, J ¼ 5.7 Hz), 2.51 (s, H), 2.61–2.69 (m, H J
1
), 3.03
NMR (300 MHz, DMSO-d
6
): d 1.10 (d, H, J ¼ 6.6 Hz), 2.51 (m,
2
3
2
4
1
3 1
(
(
d, J ¼ 11.1), 5.96 (s, H), 6.74 (m, H), 9.08 (bs, H); Vmax
H), 3.00 (dd, H J
1
1
¼ 4.5 Hz, J ¼ 13. Hz), 3.35 (m, H), 3.77
2
3
1
KBr) 3568–3340, 3260–2829, 1361, 1257, 1045, 948,
(s, H), 6.62 (dd, H, J
1
¼ 7.9 Hz, J ¼ 1.9 Hz), 6.73 (d, H,
2
À1
1
2 1
8
10 cm ; Anal. calcd. for C11
H
16ClNO
2
: C, 57.52; H, 7.02;
J ¼ 7.9 Hz), 6.81 (d, H, J ¼ 1.9 Hz), 8.7 (bs, H), 8.89 (bs, H).
N, 6.10: found C, 57.89; H, 6.97; N, 6.20.
Similarly, use of ammonium acetate (2.24 g, 29.1 mmol),
4
-hydroxy-3-methoxyphenylacetone (1.50 g, 8.3 mmol) and
1
DMMA. (58% yield) H NMR (300 MHz, DMSO-d
6
): d 1.06
sodium cyanoborohydride (0.86 g, 13.7 mmol) afforded
3
5
1
1
(
d, H, J ¼ 6.6 Hz), 2.47–2.59 (m, H), 3.08 (dd, H, J ¼ 9.1,
HMA.HCl as
a
white powder (0.65 g, 36%):
H NMR
41
3
3
1
3
3
6
2
1
8
.9 Hz), 3.69 (s, H), 3.72 (s, H), 6.72 (dd, H, J ¼ 6.4, 1.8 Hz),
(300 MHz, DMSO-d
6
): d 1.11 (d, H, J¼ 6.6 Hz), 2.50 (m, H),
2
1
1
1
.84–6.88 (m, H), 9.08 (bs, H); Vmax (KBr) 3625–3223, 2962,
2.85 (dd, H J
1
¼ 5.7 Hz, J
2
¼ 13.5 Hz), 3.43 (m, H), 3.77 (s,
3
1
1
834, 2455, 1591, 1577, 1529, 1458, 1272, 1238, 1161, 1142,
H), 6.61 (dd, H, J
1
¼ 7.9 Hz, J
2
¼ 1.9 Hz), 6.73 (d, H,
À1
1
3
1
035, 804 cm ; Anal. calcd. for C12
H
20ClNO
2
: C, 58.64; H,
J ¼ 7.9 Hz), 6.79 (d, H, J ¼ 1.9 Hz), 7.85 (bs, H), 8.87 (bs, H).
2,5-Dimethoxy-4-bromophenylethylamine was prepared
in three steps from 2,5-dimethoxybenzaldehyde according
to the methods of Varma and Kabalka (1985) and Anderson
et al. (1987). Nitroethane (4.51 g, 60.17 mmol) was added to
.20; N, 5.72: found C, 58.21; H, 8.11; N, 5.56.
1
BDB. (46% yield) H NMR (300 MHz, DMSO-d
6
): d 0.88
3
2
1
(
(
t, H, J ¼ 7.5 Hz), 1.42–1.53 (m, H), 2.41 (m, H), 2.62–2.78
1 1 2 3
m, H), 2.79–2.86 (m, H), 5.96 (s, H), 6.62–6.84 (m, H),
a
solution of 2,5-dimethoxybenzaldehyde (10.00 g,
2
8
1
.05 (bs, H); Vmax (KBr) 3629–3262, 2960, 2789, 1589, 1243,
60.17 mmol) in methanol (200 ml). After stirring for
10 min, the reaction mixture was cooled to 0 1C and sodium
hydroxide (4 ml of 10.5 M) was added dropwise over a 30-min
period. The reaction was allowed to stir at room temperature
À1
159, 1150, 1140, 795 cm ; Anal. calcd. for C11
H
15ClNO
2
:
C, 57.77; H, 6.61; N, 6.12: found C, 58.08; H, 6.78; N, 6.09.
1
3
MBDB. (58% yield) H NMR (300 MHz, DMSO-d
6
): d 0.86
for H and was then added slowly to an HCl solution
3
2
1
(
t, H, J ¼ 7.5 Hz), 1.50–1.60 (m, H), B2.50 (m, H), 2.62–
maintained at 60 1C. A yellow crystalline material formed,
which was filtered and dried to afford (E)-1-(2,5-dimethoxy-
phenyl)-2-nitroethane (16.00 g, 89% yield) as yellow crystals
(m. p. 121–123 1C).
1
1
2
2
2
6
2
.79 (m, H), 2.91–2.96 (m, H), 3.98 (s, H), 6.01 (s, H),
3
1
.71–6.98 (m, H), 9.37 (bs, H); Vmax (KBr) 3629–3262, 2960,
À1
789, 1589, 1243, 1159, 1150, 1140, 795 cm ; Anal. calcd.
for C12
H
17ClNO
2
: C, 59.38; H, 7.05; N, 5.78: found C, 59.12;
Sodium borohydride (4.29 g, 113.5 mmol) was stirred in
tetrahydrofuran (100 ml) and to this boron trifluoride
etherate (18.2 ml, 143.4 mmol) was added and the resulting
mixture was stirred at room temperature for 15 min.
Then, (E)-1-(2,5-dimethoxyphenyl)-2-nitroethane (4.50 g,
21.4 mmol) in tetrahydrofuran (60 ml) was added dropwise
over 30 min and the resulting mixture was refluxed for 4 h.
After allowing the reaction to cool to room temperature, the
reaction was quenched by careful addition of ice water
(250 ml) and acidification with concentrated HCl and
further heating at 80–85 1C for 2 h. The mixture was again
allowed to cool to room temperature and the acidic layer was
washed with diethyl ether (2 ꢀ 50 ml). The amine product
was liberated through the addition of sodium hydroxide
(30% solution) and was extracted into diethyl ether
(3 ꢀ 30 ml). The combined organic extracts were dried over
magnesium sulphate and concentrated to afford 2,5-
dimethoxyamphetamine (1.20 g, 31% yield) as a pale brown
oil.
H, 6.98; N, 5.83.
1
MDOH. (76% yield) H NMR (300 MHz, DMSO-d
6
): d 1.07
3
1
1
(
d, H, J ¼ 6.6 Hz), 2.45–2.47 (m, H), 3.05–3.15 (m, H),
1
2
3
3
.40–3.52 (m, H), 5.96 (s, H), 6.65–6.84 (m, H), 10.86 (bs,
1
1
H), 11.45 (bs, H); Vmax (KBr) 3603–3267, 3080, 2900, 1541,
À1
1
503, 1488, 1442, 1247, 1033, 927, 805 cm ; Anal. calcd. for
10 3
C H14NO Cl: C, 51.84; H, 6.09; N, 6.05: found C, 51.67;
H, 5.96; N, 5.88.
The MDMA metabolites, HMA and HMMA, were prepared
according to the method of Forsling et al. (2002) described in
procedure B.
Procedure B. To a solution of methylamine hydrochloride
(2.60 g, 38.5 mmol) in methanol (25 ml), 4-hydroxy-3-meth-
oxyphenylacetone (2.00 g, 11.1 mmol) was added and the
solution was stirred at room temperature for 3.5 h. After the
addition of sodium cyanoborohydride (0.86 g, 13.7 mmol),
the white suspension was stirred for 2 days at room
temperature under an atmosphere of nitrogen. The pH was
maintained between 4 and 6 by careful addition of hydro-
chloric acid mixed with methanol. The solution was then
2,5-Dimethoxyamphetamine (1.10 g, 6.06 mmol) was dis-
solved in acetic acid (1.5 ml) at room temperature and
bromine (1.06 g, 6.6 mmol) dissolved in acetic acid (1.5 ml)
was carefully added. After reaction for 5 min, solids were
British Journal of Pharmacology (2007) 152 1121–1130