Novel Potent Ligands for the Central nAChR
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2223
1H NMR (DMSO-d6): δ 8.90 (1H, s), 7.80 (1H, s), 7.28 (1H, s),
6.41 (3H, s), 3.17 (4H, m), 2.89 (4H, m). Anal. (C9H12ClN3‚
1.5C4H4O4) C, H, N.
s) 3.65 (2H, t J ) 4 Hz), 3.60 (2H, t J ) 6 Hz), 3.10 (2H, bt J
) 4 Hz), 3.00 (2H, bt J ) 4 Hz), 2.00 (2H, b), 1.40 (9H, s).
1-tert-Butoxycarbonyl-4-(5-(3-aminophenyl)-3-pyridyl)ho-
mopiperazine (2.0 g, 5.4 mmol) was treated according to
procedure B which afforded 98% of 9 (1.42 g, 5.3 mmol). The
corresponding fumaric acid salt was obtained by addition of a
diethyl ether and methanol mixture (9:1) saturated with fu-
maric acid; mp 207-209 °C. 1H NMR (DMSO-d6): δ 8.10 (1H,
s), 8.00 (1H, s), 7.13 (2H, m), 6.80 (1H, s), 6.77 (1H, d J ) 8.9
Hz), 6.55 (1H, d J ) 8.9 Hz), 6.40 (2H, s), 3.70 (2H, t J ) 4
Hz), 3.59 (2H, t J ) 6 Hz), 3.12 (2H, bt J ) 4 Hz), 2.96 (2H, bt
J ) 4 Hz), 2.00 (2H, b). Anal. (C16H20N4‚C4H4O4) C, H, N.
3-Ch lor o-5-eth ylen oxyp yr id in e (10a ). To a solution of
15a (5.0 g, 29 mmol) in tetrahydrofuran was added thionyl
chloride (42 g, 0.36 mol). The mixture was stirred at 50 °C for
30 min and thionyl chloride was evaporated. Water was added
and the mixture was extracted with dichloromethane. The
crude product was dissolved in ethanol (5 mL) and aqueous
potassium hydroxide (5 mL, 4 M) and was stirred at 80 °C for
18 h. Water was added and the mixture was extracted with
ethyl acetate. Chromatography gave 11% of 10a (0.51 g, 3.2
mmol). 1H NMR (CDCl3): δ 8.40 (1H, s), 8.35 (1H, s), 7.40 (1H,
s), 6.82 (1H, dd J ) 14, 7 Hz), 4.98 (1H, dd J ) 14, 1.5 Hz),
4.60 (1H, dd J ) 7, 1.5 Hz).
1-(5-Eth ylen oxy-3-p yr id yl)h om op ip er a zin e (10). P r o-
ced u r e F . A mixture of 10a (0.51 g, 3.3 mmol), homopipera-
zine (0.66 g, 6.6 mmol), potassium tert-butoxide (0.74 g, 6.6
mmol) and 1,2-dimethoxyethane (25 mL) was stirred at reflux
for 3 h. Aqueous sodium hydroxide was added and the mixture
was extracted with ethyl acetate. Chromatography gave 81%
of 10 (0.59 g, 2.7 mmol). The corresponding fumaric acid salt
was obtained by addition of a diethyl ether and methanol mix-
ture (9:1) saturated with fumaric acid; mp 174-175 °C. 1H
NMR (DMSO-d6): δ 7.92 (1H, s), 7.69 (1H, s), 6.95 (1H, dd J
) 13.7, 6.8 Hz), 6.72 (1H, s), 6.42 (3H, s), 4.77 (1H, dd J )
13.7, 1.3 Hz), 4.49 (1H, dd J ) 6.8, 1.3 Hz), 3.71 (2H, t J )
4.5 Hz), 3.55 (2H, t J ) 5.7 Hz), 3.17 (2H, bt J ) 5 Hz), 3.04
(2H, bt J ) 5 Hz), 2.02 (2H, b). Anal. (C12H14N3O‚1.5C4H4O4)
C, H, N.
5-(3-P yr id yl)-3-ch lor op yr id in e (11a ). P r oced u r e G. To
a solution of 3,5-dichloropyridine (15.0 g, 0.10 mol), diethyl-
3-pyridylborane (14.9 g, 0.10 mol) and PdCl2PPh3(CH2)3PPh3
(0.60 g, 1.0 mmol) in 1,2-dimethoxyethane (150 mL) was added
aqueous potassium carbonate (152 mL, 0.31 mol) and the
mixture refluxed for 4 days. Aqueous sodium hydroxide was
added, 1,2-dimethoxyethane was evaporated and the water
phase was extracted with ethyl acetate. Chromatography
afforded 11% of 11a (2.2 g, 11.3 mmol) as crystals; mp 98-
100 °C. 1H NMR (CDCl3): δ 8.80 (1H, s), 8.65 (2H, m), 8.50
(1H, s), 7.95 (1H, m), 7.81 (1H, bs), 7.52 (1H, m).
3-Ch lor o-5-eth oxyp yr id in e (7a ) was prepared according
to procedure D using 3,5-dichloropyridine (10 g, 68 mmol) and
sodium ethoxide (5.5 g, 81 mmol), giving 91% of 7a (8.7 g, 61
mmol). 1H NMR (CDCl3): δ 8.20 (2H, m), 7.21 (1H, s), 4.09
(2H, q J ) 7.3 Hz), 1.43 (3H, t J ) 7.3 Hz).
1-(5-Eth oxy-3-p yr id yl)p ip er a zin e (7). A mixture of 7a
(6.5 g, 45.8 mmol), piperazine (19.7 g, 229 mmol), potassium
tert-butoxide (11.2 g, 91.6 mmol) and 1,2-dimethoxyethane (150
mL) was stirred at reflux for 1 h. Aqueous sodium hydroxide
was added and the mixture was extracted with ethyl acetate.
Chromatography gave 48% of 7 (4.6 g, 22.0 mmol). The
corresponding fumaric acid salt was obtained by addition of a
diethyl ether and methanol mixture (9:1) saturated with
fumaric acid; mp 160.0-161.2 °C. 1H NMR (DMSO-d6): δ 8.29
(1H, d J ) 2.2 Hz), 7.98 (1H, d J ) 4.9 Hz), 7.31 (1H, bd J )
8.1 Hz), 7.20 (1H, dd J ) 8.1, 4.9 Hz), 6.43 (2H, s), 4.11 (2H,
q J ) 7.1 Hz), 3.18 (4H, m), 2.92 (4H, m), 1.30 (3H, t J ) 7.1
Hz). Anal. (C9H13N3‚C4H4O4) C, H, N.
1-(3-P yr id yl)h om op ip er a zin e (8). P r oced u r e E. A mix-
ture of 3-bromopyridine (3.95 g, 25 mmol), 1-tert-butoxycar-
bonylhomopiperazine (5.0 g, 25 mmol), tetrakis(triphenylphos-
phine)palladium(0) (145 mg, 0.13 mmol), potassium tert-
butoxide (6.1 g, 50 mmol) and anhydrous toluene (75 mL) was
stirred at 80 °C for 4 h. Water was added and the mixture
was extracted with ethyl acetate. Chromatography gave 13%
of 8a (0.92 g, 3.3 mmol) as a clear oil. 1H NMR (CDCl3): δ
8.03 (1H, d J ) 4 Hz), 7.81 (1H, bs), 7.03 (1H, m), 6.90 (1H,
m), 3.45 (4H, m), 3.23 (2H, bt J ) 7.1 Hz), 3.14 (2H, bt J ) 7.1
Hz), 1.85 (2H, m), 1.38 (9H, s).
8a was treated as described in procedure B which gave 85%
of 8 (0.50 g, 2.8 mmol) as an oil. The corresponding fumaric
acid salt was obtained by addition of a diethyl ether and
methanol mixture (9:1) saturated with fumaric acid; mp
172.1-172.9 °C. 1H NMR (DMSO-d6): δ 8.14 (1H, s), 7.87 (1H,
J ) 4.5 Hz), 7.13 (2H, m), 6.40 (3H, s), 3.68 (2H, m), 3.55 (2H,
m), 3.10 (2H, m), 2.98 (2H, m), 1.95 (2H, m). Anal. (C10H15N3‚
1.5C4H4O4) C, H, N.
1-(5-(3-Am in op h en yl)-3-p yr id yl)h om op ip er a zin e (9). A
solution of 14 (71.6 g, 0.27 mol) in dichloromethane (1.0 l) was
added to aqueous sodium hydrogen carbonate (1.3 l, 1 M) and
di-tert-butyl dicarbonate (58.7 g, 0.27 mol). The mixture was
stirred for 18 h at room temperature. The organic phase was
concentrated and purified by chromatography to give 52% of
1-tert-butoxycarbonyl-4-(5-hydroxy-3-pyridyl)homopipera-
zine (41.2 g, 0.14 mol) as a yellow oil. 1H NMR (CDCl3): δ
8.05 (1H, s), 7.88 (1H, s), 6.83 (1H, s), 3.55 (4H, m), 3.38 (2H,
bs), 3.22 (2H, bs), 1.92 (2H, bs), 1.39 (9H, s).
1-(5-(3-P yr idyl)-3-pyr idyl)h om op ip er a zin e (11) was pre-
pared according to procedure F using 11a (2.2 g, 11.3 mmol)
as reagent, giving 17% of 11 (0.48 g, 1.9 mmol). The corre-
sponding fumaric acid salt was obtained by addition of a
diethyl ether and methanol mixture (9:1) saturated with
fumaric acid; mp 160-162 °C. 1H NMR (DMSO-d6): δ 8.81
(1H, d J ) 3 Hz), 8.47 (1H, dd J ) 4.4, 2 Hz), 8.08 (2H, m),
8.00 (1H, dt J ) 8.5, 2 Hz), 7.38 (1H, dd J ) 8.5, 4.4 Hz), 7.28
(1H, bs), 6.41 (1H, s), 3.66 (2H, t J ) 4 Hz), 3.49 (2H, t J ) 6.0
Hz), 3.08 (2H, bt J ) 4 Hz), 2.92 (2H, bt J ) 4 Hz) 1.92 (2H,
b). Anal. (C15H18N4‚0.5C4H4O4) C, H, N.
1-tert-Butoxycarbonyl-4-(5-hydroxy-3-pyridyl)homopipera-
zine (41.0 g, 0.14 mol) was dissolved in dichloromethane and
trifluoromethanesulfonic anhydride (39.4 g, 0.14 mol) and
pyridine (33.2 g, 0.42 mol) were added at 0 °C. The mixture
was allowed to warm overnight, washed with aqueous sodium
hydroxide and concentrated. Chromatography afforded 28%
of 1-tert-butoxycarbonyl-4-(5-trifluoromethanesulfonyloxy-3-
1
pyridyl)homopiperazine (16.7 g, 39 mmol). H NMR (CDCl3):
δ 8.12 (1H, s), 7.90 (1H, s), 6.87 (1H, bs), 3.62 (4H, m), 3.38
(2H, bt), 3.28 (2H, bt), 1.96 (2H, m), 1.39 (9H, s).
3-Br om o-5-th iop h en ylp yr id in e (12a ) was synthesized by
procedure D using 3,5-dibromopyridine (10.0 g, 42.4 mmol),
thiophenol (4.7 g, 42.2 mmol), sodium hydride (1.9 g of a 60%
suspension, 46.4 mmol) as base and N,N-dimethyl form-
amide as solvent. This gave 99% of 12a (11.2 g, 42.0 mmol).
1H NMR (CDCl3): δ 8.51 (1H, bs), 7.69 (1H, bs), 7.40 (5H, m),
6.85 (1H, bs).
1-(5-Th iop h en yl-3-p yr id yl)h om op ip er a zin e (12). P r o-
ced u r e H. A mixture of 3-bromo-5-thiophenylpyridine (6.0 g,
22.5 mmol), homopiperazine (11.3 g, 113 mmol), tetrakis-
(triphenylphosphine)palladium(0) (260 mg, 0.23 mmol), potas-
sium tert-butoxide (5.1 g, 45 mmol) and anhydrous toluene (60
mL) was stirred at 80 °C for 4 h. Water was added and the
1-tert-Butoxycarbonyl-4-(5-trifluoromethanesulfonyloxy-3-
pyridyl)homopiperazine (2.0 g, 4.7 mmol) was dissolved in 1,2-
dimethoxyethane (35 mL) and 1,3-propanediol (1.8 g, 23.5
mmol), lithium chloride (0.61 g, 14.1 mmol), aqueous potas-
sium carbonate (14.1 mL, 28.2 mmol), tetrakis(triphenylphos-
phine)palladium(0) (0.16 g, 0.10 mmol) and 3-aminophenyl-
boronic acid hemisulfate (1.31 g, 7.1 mmol) were added. The
mixture was refluxed for 1 h, added to aqueous sodium
hydroxide and extracted with ethyl acetate. Chromatography
afforded 85% of 1-tert-butoxycarbonyl-4-(5-(3-aminophenyl)-
3-pyridyl)homopiperazine (1.5 g, 4.0 mmol). 1H NMR
(CDCl3): δ 8.12 (1H, s), 8.01 (1H, s), 7.21 (2H, m), 6.81 (1H,
s), 6.72 (1H, d J ) 9.3 Hz), 6.55 (1H, d J ) 9.3 Hz), 6.4 (1H,