Structure-Activity Studies of Piperidine Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 659
Biotech Inc. (Piscataway, NJ ). Cocaine hydrochloride was
purchased from Mallinckrodt Chemical Corp. (St. Louis, MO).
WIN 35 428 naphthalene sulfonate was purchased from
Research Biochemicals, Inc. (Natick, MA). (-)-Cocaine HCl
was obtained from the National Institute on Drug Abuse. GBR
12909 dihydrochloride (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-
4-[3-phenylpropyl]piperazine) was purchased from SIGMA-
Aldrich (#D-052; St. Louis, MO).
converted into its oxalate salt; mp ) 163-165 °C; Anal. C28H33-
NO2, (COOH)2.
Syn t h esis of 4-[2-(Dip h en ylm et h oxy)et h yl]-1-[(4-io-
d op h en yl)m eth yl]p ip er id in e (4). 4-[(2-Diphenylmethoxy)-
ethyl]piperidine (0.23 g, 0.77 mmol) was reacted with 4-iodo
benzyl bromide (0.76 g, 2.5 mmol) and K2CO3 (1.00 g, 7 mmol)
in EtOH (10 mL) to give a thick oil, 0.17 g (46%). 1H NMR
(300 MHz, CDCl3): δ 1.21-1.63 (7H, m), 1.87-1.93 (t, J ) 11
Hz, 2H, N(CH2)-), 2.79-2.83 (bd, J ) 12 Hz, 2H, N(CH2)-),
3.41-3.49 (4H, m), 5.31 (s, 1H, Ph2CHO-), 7.05-7.63 (14H,
m, ArH). Free base was converted into its oxalate salt; mp )
160-161 °C; Anal. C27H30INO, (COOH)2.
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(4-eth y-
n ylp h en yl)m eth yl]p ip er id in e (5). To a solution of 4-[2-
(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine
(0.23 g, 0.496 mmol) in toluene (10 mL) under an N2 atmo-
sphere were added tetrakis(triphenylphosphine)palladium(0)
(30 mg, 0.026 mmol) and tributyl(ethynyl)tin (0.17 g, 0.546
mmol, 1.1 equiv), and the mixture was refluxed. After 3 h, the
color was very dark, and the reaction was completed by TLC
(4:1; hex:acetone). The solvent was evaporated, and the residue
was chromatographed to yield 0.162 g (90%) of the free base
as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 1.2-1.3 (2H,
m), 1.4-1.65 (5H, m), 1.9-2.0 (2H, m), 2.84 (2H, bd, J ) 11.2
Hz), 3.06 (1H, s), 3.4-3.5 (4H, m), 5.32 (1H, s), 7.2-7.35 (12H,
m), 7.44 (2H, d, J ) 8 Hz). The free base was converted into
its oxalate salt; mp 166-170 °C; Anal. C31H33NO5‚H2O.
P r oced u r e A. Syn th esis of 4-[2-(Dip h en ylm eth oxy)-
e t h yl]-1-[(4-m e t h oxyca r b on ylp h e n yl)-m e t h yl]p ip e r i-
d in e (3a ). A mixture of 4-[2-(diphenylmethoxy)ethyl]piperi-
dine(0.23g,0.76mmol),175mgofmethyl4-(bromomethyl)benzoate
(0.17 g, 0.76 mmol), and powdered K2CO3 (0.15 g, 1.1 mmol,
1.5 equiv) in 3 mL of EtOH was refluxed for 1 h. The solvent
was evaporated, and the residue was chromatographed (SiO2;
CH2Cl2/MeOH) to yield the free base (0.23 g, 80%) as an oil
1
that slowly crystallized (mp 91-3 °C; hexane/Et2O). H NMR
(300 MHz, CDCl3): δ 1.2-2.0 (9H, m), 2.83 (2H, bd, J ) 11.1
Hz), 3.4-3.6 (4H, m), 3.91 (3H, s), 5.31 (1H, s), 7.07 (2H, d, J
) 7.8 Hz), 7.2-7.39 (10H, m), 7.39 (2H, d, J ) 7.8 Hz), 7.97
(2H, d, J ) 7.8 Hz). The free base was converted into its oxalate
salt; mp 129-133 °C; Anal. C31H35NO7.
4-[(2-Dip h en ylm eth oxy)eth yl]-1-(1-n a p h th ylm eth yl)p i-
p er id in e (3b). 4-[(2-Diphenylmethoxy)ethyl]piperidine (0.18
g, 0.61 mmol) was reacted with 2-bromo methylnaphthalene
(0.21 g, 0.95 mmol) and K2CO3 (0.85 g, 0.61 mmol) in EtOH
(10 mL) to give a thick oil, 0.25 g (96%), procedure A. 1H NMR
(300 MHz, CDCl3): δ 1.22-1.33 (2H, m), 1.48-1.53 (1H, m),
1.58-1.66 (4H, m), 1.66-2.02 (2H, dt, J ) 1.6, 11.2 Hz,
N(CH)2), 2.89-2.92 (2H, bd, J ) 11.2 Hz, N(CH)2), 3.47-3.50
(2H, t, J ) 6.4 Hz, OCH2), 3.65 (2H, s, NCH2Ar), 5.32 (1H, s,
Ph2CHO), 7.22-7.35 (10H, m, ArH), 7.43-7.51 (3H, m, ArH),
7.74 (1H, s, ArH), 7.81 (2H, m, ArH). Free base was converted
into its oxalate salt; mp ) 194-195 °C; Anal. C31H33NO,
(COOH)2.
4-[(2-Dip h en ylm eth oxy)eth yl]-1-(2-n a p h th ylm eth yl)p i-
p er id in e (3c). 4-[(2-Diphenylmethoxy)ethyl]piperidine (0.11
g, 0.37 mmol) was reacted with 1-chloro methylnaphthalene
(0.12 g, 0.68 mmol) and K2CO3 (0.52 g, 3.77 mmol) in EtOH
(10 mL) to give a thick oil, 0.14 g (86%), procedure A. 1H NMR
(300 MHz, CDCl3): δ 1.20-1.29 (2H, m), 1.51-1.54 (1H, m),
1.55-1.63 (4H, m), 2.01-2.07 (2H, t, J ) 12 Hz, N(CH)2),
2.91-2.95 (2H, bd, J ) 12 Hz, (NCH)2), 3.88 (2H, s, NCH2Ar),
5.33 (1H, s, Ph2CHO), 7.23-7.55 (13H, m, ArH), 7.76-7.78
(1H, d, J ) 8.0 Hz, ArH), 7.84-7.87 (1H, d, J ) 9.6 Hz, ArH),
8.31-8.33 (1H, d, J ) 8.0 Hz, ArH). Free base was converted
into its oxalate salt; mp ) 158-160 °C; Anal. C31H33NO,
(COOH)2.
4-[(2-Dip h en ylm eth oxy)eth yl]-1-[((4-isop r op yl)p h en yl-
)m eth yl]piper idin e (3d). A mixture of 4-[(2-diphenylmethoxy)-
ethyl]piperidine (0.18 g, 0.61 mmol), 4-isopropylbenzyl chloride
(0.19 g, 1.13 mmol), and K2CO3 (0.85 g, 6.16 mmol) in EtOH
(10 mL) was stirred at 50 °C for 6 h. The mixture was filtered,
and the organic phase was evaporated to give the crude
product, which was purified by flash chromatography (EtOAc/
Hexane ) 1/5) to give a thick oil, 0.21 g (80%), procedure A.
1H NMR (300 MHz, CDCl3): δ 1.21-1.28 (2H, m), 1.23-1.25
(6H, d, J ) 6.4 Hz, (CH3)2CH), 1.42-1.50 (1H, m), 1.56-1.61
(4H, m), 1.87-1.93 (2H, t, J ) 11.2 Hz, N(CH)2), 2.83-2.90
(3H, m, N(CH)2, PhCH(CH3)2), 3.44 (2H, s, NCH2Ar), 3.45-
3.48 (2H, t, J ) 6.4 Hz, -OCH2 ), 5.31 (1H, s, Ph2CHO), 7.15-
7.34 (14H, m, ArH). Free base was converted into its oxalate
salt; mp ) 118-120 °C; Anal. C30H37NO, (COOH)2‚0.2H2O.
4-[(2-Diph en ylm eth oxy)eth yl]-1-[((3-m eth oxyl)ph en yl)-
m eth yl]p ip er id in e(3e). 4-[(2-Diphenylmethoxy)ethyl]piperi-
dine (0.15 g, 0.50 mmol) was reacted with 3-methoxy benzyl
bromide (0.13 g, 0.65 mol) and K2CO3 (0.52 g, 3.77 mmol) in
EtOH (10 mL) to give a thick oil, 0.18 g (86%), procedure A.
1H NMR (300 MHz, CDCl3): δ 1.20-1.30 (2H, m), 1.46-1.50
(1H, m), 1.51-1.64 (4H, m), 1.87-1.93 (2H, t, J ) 12 Hz,
N(CH)2), 2.84-2.87 (2H, bd, J ) 12 Hz, N(CH)2), 3.46-3.50
(4H, m, OCH2, NCH2Ph), 3.81 (3H, s, OCH3), 5.33 (1H, s, Ph2-
CHO), 6.79-6.81 (1H, d, J ) 8.0 Hz, ArH), 6.90-6.92 (1H, d,
J ) 8.0 Hz, ArH), 7.21-7.36 (12H, m, ArH). Free base was
Syn t h esis of 4-[2-(Dip h en ylm et h oxy)et h yl]-1-[(4-vi-
n ylp h en yl)m eth yl]p ip er id in e (6). To a solution of 4-[2-
(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine (0.2
g, 0.384 mmol) in toluene (10 mL) under a nitrogen atmosphere
were added tetrakis(triphenylphosphine)palladium(0) (30 mg,
0.026 mmol) and tributyl(vinyl)tin (0.12 g, 0.38 mmol, 1 equiv),
and the mixture was refluxed. After 4 h, the color was very
dark, and the reaction was completed by TLC (4:1; hexane:
acetone). The mixture was filtered through Celite, then the
solvent was evaporated, and the residue was chromatographed
1
to yield 0.14 g (86%) of the free base as a pale yellow oil. H
NMR (CDCl3, 400 MHz): δ 1.2-2.1 (9H, m), 2.93 (2H, bs), 3.46
(2H, t, J ) 6.4 Hz), 3.59 (2H, bs), 5.23 (1H, d, J ) 11.6 Hz),
5.29 (1H, s), 5.74 (1H, d, J ) 17.6 Hz), 6.7 (1H, dd, J ) 11.2
and 16 Hz), 7.19-7.4 (14H, m). The free base was converted
into its oxalate salt; mp 136-141 °C; Anal. C31H35NO5‚3/4H2O.
Syn t h esis of 4-[2-(Dip h en ylm et h oxy)et h yl]-1-[(4-(2-
p r op en yl)p h en yl)m eth yl]p ip er id in e (7). To a stirred solu-
tion of 2-bromopropene (0.69 g, 5.76 mmol, 3 equiv) in 4 mL
of tetrahydrofuran (THF) at -78 °C was added dropwise 2.88
mL of 2 M n-BuLi in pentane (17.28 mmol, 3 equiv). After the
solution was stirred for 15 min, 3.84 mL of 0.5 M ZnCl in THF
(17.28 mmol, 3 equiv) was added and the solution remained
stirring at -78 °C for a further 30 min. Then, 4-[2-(diphenyl-
methoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine (1 g, 1.92
mmol) dissolved in 2 mL of THF was added dropwise to the
solution followed by dichlorobis(triphenylphosphine) palla-
dium(II) (100 mg, 0.14 mmol). The mixture was stirred at -78
°C for 2 h, and then, the cooling bath was removed and allowed
to warm and stir at room temperature for 12 h. The solvent
was evaporated, and the residue was chromatographed (SiO2;
hexane:acetone) to furnish the free base (0.33 g, 40%) as a pale
yellow oil. 1H NMR (CDCl3, 400 MHz): δ 1.2-2.0 (9H, m), 2.8-
2.9 (2H, bs), 3.46 (2H, t, J ) 6.8 Hz), 3.55 (2H, bs), 5.07 (1H,
s), 5.30 (1H, s), 5.36 (1H, s), 7.2-7.35 (13H, m), 7.42 (1H, d, J
) 8.4 Hz). The free base was converted into oxalate salt; mp
128-132 °C; Anal. C32H35NO5‚1.5 H2O.
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(4-p r o-
p yn ylp h en yl)m eth yl]p ip er id in e (8). A mixture of 4-[2-
(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine (0.5
g, 0.96 mmol), 1-(trimethylsilyl)-1-propyne (0.12 g, 1.15 mmol,
1.2 equiv), tetrakis(triphenylphosphine)palladium(0) (110 mg,
10 mol %), tetrabutylammonium fluoride (0.25 g, 1.2 equiv),
and 52 mg of ethanol (1.2 equiv) in 10 mL of THF was heated
to 50 °C for 2 h. Saturated K2CO3 was added, and the mixture
was extracted thrice with CH2Cl2. These were collected, dried
(MgSO4), and evaporated to a brown oil. The oil was chro-