1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3079
compound as a white powder; mp 155-156 °C. 1H NMR
(D2O): δ 1.80 (t, 2H, CH2), 2.52-2.61 (m, 4H, CH2CH2), 2.87-
2.88 (m, 2H, CH2), 3.13 (t, 2H, CH2), 3.71 (s, 3H, OCH3), 3.74
(s, 3H, OCH3), 6.81-6.85 (m, 2H, Ar-H), 7.15-7.29 (m, 5H,
Ar-H); IR (KBr pellet): 2955 (NH+) cm-1. Anal. Calcd. for
(C19H26ClNO2) C, H, N.
(()1-[2-Met h oxy-4-(3-p h en ylp r op yl)p h en yl]-2-a m in o-
p r op a n e HCl (12). Compound 12 was prepared from 49 in
the same manner as 18. The crude free amine was converted
immediately to the HCl salt using ethereal HCl. The white
solid was recrystallized from 2-PrOH to give 0.19 g (45%) of
12; mp 134-136 °C. 1H NMR (D2O): δ 1.17 (d, 3H, CH3), 1.77-
1.85 (m, 2H, CH2), 2.47-2.53 (m, 4H, CH2, CH2), 2.79 (d, 2H,
CH2), 3.49-3.55 (m, 1H, CH), 3.70 (s, 3H, OCH3), 6.69 (d, 1H,
Ar-H), 6.75 (s, 1H, Ar-H), 7.02 (d, 1H, Ar-H), 7.10-7.25 (m,
5H, Ar-H); IR (KBr pellet): 2922 (NH+) cm-1. Anal. Calcd.
for (C19H26ClNO) C, H, N.
2-[2,5-Dim et h oxy-4-(4-p h en ylb u t yl)p h en yl]-1-a m in o-
eth a n e HCl (7). A solution of 40 (0.20 g, 0.49 mmol) in 15%
NaOH (15 mL) and MeOH (10 mL) was heated at reflux for 2
h. The MeOH was removed under reduced pressure and the
aqueous solution was extracted with Et2O (4 × 50 mL). The
ethereal solution was dried (MgSO4), and solvent was removed
under reduced pressure. The oil was dissolved in anhydrous
Et2O and ethereal HCl was added to form the salt, which was
recrystallized from 2-PrOH to give 0.08 g (47%) of 7 as a white
powder; mp 172-174 °C. 1H NMR (D2O): δ 1.30-1.45 (m, 4H,
CH2CH2), 2.30-2.40 (m, 4H, CH2CH2), 2.79 (t, 2H, CH2), 3.04
(t, 2H, CH2), 3.48 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 6.48 (s,
1H, Ar-H), 6.72 (s, 1H, Ar-H), 6.91-7.03 (m, 5H, Ar-H); IR
(KBr pellet): 2936 (NH+) cm-1. Anal. Calcd. for (C20H28ClNO2)
C, H, N.
(()1-[3-Met h oxy-4-(3-p h en ylp r op yl)p h en yl]-2-a m in o-
p r op a n e HCl (13). Compound 13 was prepared from 52 using
the same procedure used for the synthesis of 18. The HCl salt
was obtained and recrystallized from 2-PrOH/anhydrous Et2O
1
to give 0.17 g (23%) of 13; mp 107-109 °C. H NMR (D2O): δ
1.12 (d, 3H, CH3), 1.65 (quintet, 2H, CH2), 2.34-2.40 (m, 4H,
CH2, CH2), 2.66 (dd, 1H, CH2), 2.89 (dd, 1H, CH2-b), 3.43 (m,
1H, CH), 3.60 (s, 3H, OCH3), 6.59 (d, 1H, Ar-H), 6.74 (s, 1H,
Ar-H), 6.83 (d, 1H, Ar-H), 7.03 (m, 5H, Ar-H); IR (KBr
pellet): 2939.6 (NH+) cm -1. Anal. Calcd. for (C19H26ClNO) C,
H, N.
(()1-[2,5-Dim eth oxy-4-(4-ph en ylbu tyl)ph en yl]-2-am in o-
p r op a n e HCl (8). Compound 8 was obtained from 41 in the
same manner used for the synthesis of 7. The resulting crude
solid material was recrystallized from absolute EtOH to give
0.40 g (18%) of the desired compound; mp 111-113 °C. 1H
NMR (CDCl3): δ 2.93 (t, 2H, CH2), 3.57 (t, 2H, CH2), 3.81 (s,
3H, OCH3), 3.88 (s, 3H, OCH3), 4.32 (s, 2H, CH2), 6.76 (s, 1H,
Ar-H), 6.99 (bs, 1H, NH), 7.21-7.31 (m, 6H, Ar-H); IR
(film): 3314 (NH), 1709 (CdO, amide), 1671 (CdO, ketone)
cm-1. Anal. Calcd. for (C20H20F3NO4) C, H, N.
(()1-[2,3-Dim ethoxy-4-(3-ph en ylpr opyl)ph en yl]-2-am in o-
p r op a n e Hem ioxa la te (14). At 0 °C and under N2, dry THF
(5 mL) was added to LiAlH4 (0.14 g, 3.67 mmol), followed by
the addition of nitropropene 59 (0.29 g, 0.85 mmol) in dry THF
(7 mL). The reaction mixture was heated at reflux for 1 h, then
cooled to 0 °C. Excess LiAlH4 was decomposed by the addition
of H2O (0.2 mL), 10% NaOH (0.2 mL), and H2O (1 mL). The
salts were removed by filtration, and the filtrate was diluted
with Et2O (25 mL) and dried (MgSO4); removal of the solvents
under reduced pressure gave a clear oil. Preparation of the
HCl salt was unsuccessful. The oxalate salt was prepared and
recrystallized from 2-PrOH to give 0.05 g (16%) of 14; mp 228-
(()1-[2,5-Dim eth oxy-4-(3-(4-ch lor o)ph en ylpr opyl)ph en -
yl]-2-a m in op r op a n e HCl (9). Compound 9 was prepared
from 2913 in a manner similar to that of compound 4, except
that a Wolff-Kishner reduction was used to reduce the
intermediate ketone. Acylation of 29 with 3-(4-chlorophenyl)-
propionyl chloride afforded (()N-trifluoroacetyl-1-[2,5-dimeth-
oxy-4-(3-(4-chloro)phenylpropionyl)phenyl]-2-aminopropane in
68% yield; mp 160-163 °C after recrystallization from aqueous
EtOH. This compound (1.16 g, 2.54 mmol) in diethylene glycol
(10 mL) was added to a preheated (150 °C) solution of KOH
(4.2 g) and 97% hydrazine (7.3 mL) in diethylene glycol (18
mL). The stirred mixture was heated at this temperature for
2 h; H2O (10 mL) and MeOH (10 mL) were added, and the
reaction mixture was heated at reflux overnight. Once cool,
the reaction mixture was extracted with CH2Cl2 (3 × 50 mL);
the organic solvent was removed under reduced pressure, and
the oily product was purified by distillation (bp 90 °C, 0.05
mmHg) to give 0.52 g (59%) of the target compound as its free
base. The product was converted to its HCl salt, 9; mp 164-
166 °C after recrystallization from an absolute EtOH/anhy-
drous Et2O mixture. 1H NMR (DMSO-d6): δ 1.10 (d, 3H, CH3),
1.85 (m, 2H, CH2), 2.70 (m, 6H, CH2), 3.51 (m, 1H, CH), 3.70
(s, 6H, OCH3), 6.80 (s, 2H, ArH), 7.25 (m, 4H, ArH), 8.10 (bs,
3H, NH+); IR (KBr pellet): 2931 (NH+) cm-1. Anal. Calcd. for
(C20H27Cl2NO2) C, H, N.
1
230 °C. H NMR (DMSO-d6): δ 1.01 (d, 3H, CH3), 1.77-1.88
(m, 2H, CH2), 2.53-2.72 (m, 6H, CH2, CH2, CH2), 3.13-3.21
(m, 1H, CH), 3.65 (bs, 3H, NH3+), 3.71 (s, 3H, OCH3), 3.75 (s,
3H, OCH3), 6.86-6.90 (m, 2H, Ar-H), 7.17-7.31 (m, 5H, Ar-
H); IR (KBr pellet): 2946 (NH+) cm-1. Anal. Calcd. for (C20H27
-
NO2‚0.5C2H2O4) C, H, N.
(()1-[3,5-Dim ethoxy-4-(3-phen ylpr opyl)phenyl]-2-am in o-
p r op a n e HCl (15). A solution of 62 (0.43 g, 1.05 mmol) in
MeOH (15 mL) and 15% NaOH (10 mL) was heated at reflux
for 1 h. After cooling the reaction mixture to room temperature,
MeOH was removed under reduced pressure. The aqueous
solution was extracted with Et2O (3 × 50 mL), the organic
portion was dried (MgSO4), and solvent was removed under
reduced pressure to give an oil. The HCl salt was prepared
and recrystallized from 2-PrOH to give 0.27 g (73%) of 15; mp
1
158-160 °C. H NMR (D2O): δ 1.20 (d, 3H, CH3), 1.64-1.71
(m, 2H, CH2), 2.48-2.54 (m, 4H, CH2, CH2), 2.74 (dd, 1H, CH2),
2.87 (dd, 1H, CH2), 3.48-3.55 (m, 1H, CH), 3.67 (s, 6H,
(OCH3)2), 6.50 (s, 2H, Ar-H), 7.08-7.20 (m, 5H, Ar-H); IR
(KBr pellet): 2940 (NH+) cm-1. Anal. Calcd. for (C20H28ClNO2)
C, H, N.
(()1-[2,6-Dim ethoxy-4-(3-ph en ylpr opyl)ph en yl]-2-am in o-
p r op a n e HCl (16). At 0 °C under N2, dry THF (5 mL) was
added to LiAlH4 (0.21 g, 5.53 mmol), followed by the addition
of nitropropene 64 (0.50 g, 1.46 mmol) in dry THF (8 mL). The
reaction mixture was heated at reflux under N2 for 1 h, then
cooled to 0 °C (ice bath). Excess LiAlH4 was decomposed by
the addition of H2O (0.2 mL), 10% NaOH (0.2 mL), and H2O
(1 mL). The reaction mixture was filtered and washed with
Et2O (3 × 25 mL). The ethereal solution was dried (MgSO4)
and concentrated under reduced pressure to give 0.41 g (90%)
of a colorless oil. The HCl salt was prepared and recrystallized
from 2-PrOH/anhydrous Et2O to give 0.26 g (51%) of 16 as a
white powder; mp 160-162 °C. 1H NMR (D2O): δ 1.16 (d, 3H,
CH3), 1.65-1.75 (m, 2H, CH2), 2.33-2.41 (m, 4H, CH2, CH2),
2.80 (d, 2H, CH2), 3.42-3.49 (m, 1H, CH), 3.57 (s, 6H, [OCH3]2),
6.24 (s, 2H, Ar-H), 6.95-7.08 (m, 5H, Ar-H); IR (KBr
pellet): 2936 (NH+) cm-1. Anal. Calcd. for (C20H28ClNO2) C,
H, N.
(()1-[2,5-Dim et h oxy-4-(3-(4-m et h oxy)p h en ylp r op yl)-
p h en yl]-2-a m in op r op a n e HCl (10). Compound 10 was
prepared from 2913 in the same manner used for the synthesis
of 4. Acylation of 29 with 3-(4-methoxyphenyl)propionyl chlo-
ride afforded (()N-trifluoroacetyl-1-[2,5-dimethoxy-4-(3-(4-
methoxy)phenylpropionyl)phenyl]-2-aminopropane (11) in 16%
yield after distillation; bp 105-110 °C (0.05 mmHg). Catalytic
reduction of 11 and removal of the protecting group afforded
an 85% yield of the target compound (free base) as a yellow
oil. A sample was converted to the HCl salt; mp 158-160 °C
after recrystallization from an absolute EtOH/anhydrous Et2O
mixture. 1H NMR (DMSO-d6): δ 1.35 (d, 3H, CH3), 1.85 (m,
2H, CH2), 2.60 (t, 4H, CH2), 2.95 (m, 2H, CH2), 3.65 (m, 1H,
CH), 4.80 (s, 9H, OCH3), 6.60 (s, 1H, ArH), 6.70 (s, 1H, ArH),
6.82 (d, 2H, ArH), 7.10 (d, 2H, ArH), 8.30 (bs, 3H, NH+); IR
(KBr pellet): 2935 (NH+) cm-1. Anal. Calcd. for (C21H30ClNO3)
C, H, N.