5090 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Prat et al.
(3R)-3-{[(9-Methyl-9H-xanthen-9-yl)carbonyl]oxy}-1-(3-phe-
noxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (49) was pre-
pared as described for compound 44 starting from compound 16
(0.10 g, 0.28 mmol) and (3-bromopropoxy)benzene (0.30 g, 1.40
mmol). The reaction time was 72 h. Trituration with diethyl
ether gave 0.11 g (69%) of compound 49, mp 195 °C. 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.33-1.48 (m, 1 H), 1.59-1.74 (m,
1 H), 1.74-1.96 (m, 2 H), 1.92 (s, 3 H), 1.97-2.18 (m, 3 H),
2.74-2.91 (m, 1 H), 3.05-3.18 (d, J=13.7 Hz, 2 H), 3.23-3.50
(m, 5 H), 3.79-3.92 (m, 1 H), 3.97-4.07 (t, J=5.8 Hz, 2 H),
5.00-5.10 (m, 1 H), 6.91-7.02 (m, 3 H), 7.12-7.23 (m, 4 H),
7.27-7.42 (m, 4 H), 7.44-7.50 (dd, J=8.1, 1.7 Hz, 1 H), 7.50-
7.55 (dd, J = 8.1, 1.4 Hz, 1 H). HPLC (method A): 98.4%,
tR=21.3 min. MS (ESI) 484 m/z (M - Br)þ.
(3R)-3-{[(9-Methyl-9H-fluoren-9-yl)carbonyl]oxy}-1-(3-phe-
noxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (50) was pre-
pared as described for compound 44 starting from compound
17 (0.20 g, 0.6 mmol) and (3-bromopropoxy)benzene (0.64 g,
3.0 mmol). The reaction time was 72 h. Trituration with diethyl
ether gave 0.20 g (61%) of compound 50, mp 204 °C. 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.42-1.63 (m, 1 H), 1.63-1.97
(m, 3 H), 1.78 (s, 3 H), 1.97-2.25 (m, 3 H), 2.94-3.15 (m, 1 H),
3.20-3.60 (m, 6 H), 3.80-3.97 (m, 1 H), 3.96-4.18 (t, J =
5.5 Hz, 2 H), 4.91-5.05 (m, 1 H), 6.87-7.01 (m, 3 H), 7.24-
7.50 (m, 6 H), 7.62-7.70 (d, J=6.7 Hz, 1 H), 7.72-7.80 (d, J=
7.0 Hz, 1 H), 7.86-7.95 (d, J=6.7 Hz, 2 H). HPLC (method A):
99.4%, tR=20.8 min. MS (ESI) 468 m/z (M - Br)þ.
(3R)-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-methyl-1-azo-
niabicyclo[2.2.2]octane bromide (51) was prepared as described
for compound 44 starting from compound 19 (0.20 g, 0.57 mmol)
and bromomethane (2.85 mL of a 1 M solution in acetonitile,
2.85 mmol). The reaction time was 18 h. Trituration with diethyl
ether gave 0.20 g (79%) of compound 51, mp 251 °C. 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.60-1.84 (m, 2 H), 1.82-2.07
(m, 2 H), 2.29 (m, 1 H), 3.02 (s, 3 H), 3.19-3.58 (m, 5 H), 3.90-
4.03 (ddd, J=13.3, 8.4, 2.1 Hz, 1 H), 5.15-5.27 (m, 1 H), 6.97-
7.07 (dt, J=5.0, 3.8 Hz, 2 H), 7.16-7.24 (ddd, J=8.1, 3.5, 1.2 Hz,
2 H), 7.49 (s, 1 H) 7.50-7.55 (ddd, J=5.1, 3.7, 1.2 Hz, 2 H).
HPLC (method B): 99.7%, tR=7.7 min. MS (ESI) 364 m/z (M -
Br)þ.
(3R)-1-Heptyl-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-azonia-
bicyclo[2.2.2]octane bromide (52). To a solution of compound 19
(0.50 g, 1.43 mmol) in 10 mL of chloroform was added 1-
bromoheptane (1.02 g, 5.52 mmol). The mixture was stirred at
room temperature for 7 days. The solvent was evaporated, and
the residue was treated with diethyl ether. The resulting solid
was filtered and washed with diethyl ether to obtain 0.49 g (66%)
of compound 52, mp 134 °C. 1H NMR (300 MHz, DMSO-d6) δ
ppm 0.88 (t, J=6.7 Hz, 3 H), 1.16-1.39 (m, 8 H), 1.5-1.8 (m, 4
H), 1.83-2.06 (m, 2 H), 2.25-2.35 (m, 1 H), 3.03-3.54 (m, 7 H),
3.89 (ddd, J=13.9, 8.2, 1.7 Hz, 1 H), 5.16-5.29 (m, 1 H), 7.02
(ddd, J=5.1, 3.6, 2.3 Hz, 2 H), 7.17 (td, J=3.6, 1.2 Hz, 2 H), 7.49
(s, 1 H), 7.52 (ddd, J=5.1, 2.3, 1.2 Hz, 2 H). HPLC (method A):
99.5%, tR=17.9 min. MS (ESI) 448 m/z (M - Br)þ.
The reaction time was 72 h. Crystallization from acetonitrile
gave 0.18 g (59%) of compound 54, mp 216 °C. 1H NMR (300
MHz, DMSO-d6) δ ppm 1.60-1.89 (m, 2 H), 1.89-2.13 (m, 2
H), 2.27-2.40 (m, 1 H), 2.89-3.12 (m, 2 H), 3.17-3.32 (m, 1 H),
3.37-3.67 (m, 6 H), 3.92-4.08 (m, 1 H), 5.22-5.34 (m, 1 H),
7.03 (dd, J=3.4 Hz, 2 H), 7.19 (dd, J=3.7 Hz, 2 H), 7.24-7.42
(m, 5 H), 7.49 (s, 1 H), 7.54 (dd, J=3.4 Hz, 2 H). HPLC (method
A): 99.6%, tR=15.5 min. MS (ESI) 454 m/z (M - Br)þ.
(3R)-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(4-phenylbutyl)-
1-azoniabicyclo[2.2.2]octane bromide (55) was prepared as de-
scribed for compound 52 starting from compound 19 (0.50 g,
1.43 mmol) and (4-bromobutyl)benzene (1.22 g, 5.73 mmol).
The reaction time was 7 days. Trituration with diethyl ether gave
0.32 g (41%) of compound 55, mp 64 °C. 1H NMR (300 MHz,
CDCl3) δ ppm 1.50-1.72 (m, 4 H), 1.72-2.12 (m, 5 H), 2.34-
2.44 (m, 1 H), 2.61 (t, J=6.6 Hz, 2 H), 3.34-3.59 (m, 5 H), 3.60-
3.69 (m, 1 H), 3.74 (d, J=13.7 Hz, 1 H), 4.20 (dd, J=13.0, 8.4 Hz,
1 H), 5.18-5.32 (m, 1 H), 6.93 (dd, J=5.0, 3.8 Hz, 2 H), 7.09-
7.33 (m, 9 H). HPLC (method B): 98.6%, tR =12.5 min. MS
(ESI) 482 m/z (M - Br)þ.
(3R)-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypro-
pyl)-1-azoniabicyclo[2.2.2]octane bromide (56) was prepared as
described for compound 44 starting from compound 19 (5.0 g,
14.33 mmol) and (3-bromopropoxy)benzene (15.97 g, 74.23
mmol). The reaction time was 18 h. Trituration with acetoni-
trile gave 7.20 g (89%) of compound 56, mp 230 °C. 1H NMR
(300 MHz, DMSO-d6) δ ppm 1.63-1.87 (m, 2 H), 1.85-2.06
(m, 2 H), 2.06-2.24 (m, 2 H), 2.26-2.38 (m, 1 H), 3.13-3.29
(m, 1 H), 3.32-3.64 (m, 6 H), 3.91-4.07 (m, 1 H), 4.03 (t, J=5.8
Hz, 2 H), 5.19-5.31 (m, 1 H), 6.91-7.00 (m, 3 H), 7.00-7.06
(m, 2 H), 7.17-7.22 (m, 2 H), 7.28-7.36 (m, 2 H), 7.50 (s, 1H),
7.50-7.56 (m, 2 H). HPLC (method B): 99.8%, tR=11.9 min.
MS (ESI) 484 m/z (M - Br)þ.
(3R)-3-[(Di-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-1-azon-
iabicyclo[2.2.2]octane bromide (57) was prepared as described
for compound 44 starting from compound 21 (0.25 g, 0.75
mmol) and (3-bromopropoxy)benzene (0.81 g, 3.75 mmol).
The reaction time was 24 h. Trituration with diethyl ether gave
0.34 g (83%) of compound 57, mp 148 °C. 1H NMR (300 MHz,
DMSO-d6) δ ppm 1.72-2.05 (m, 4 H), 2.05-2.23 (m, 2 H),
2.25-2.36 (m, 1 H), 3.20-3.34 (m, 1 H), 3.36-3.64 (m, 4 H),
3.40-3.48 (t, J=7.9 Hz, 2 H), 3.90-4.03 (m, 1 H), 4.00-4.06 (t,
J=5.8 Hz, 2 H), 5.14-5.24 (m, 1 H), 5.91 (s, 1 H), 6.92-6.99 (m,
3 H), 6.99-7.04 (ddd, J=5.0, 3.6, 1.2 Hz, 2 H), 7.12-7.18 (dd,
J=7.3, 3.4 Hz, 2 H), 7.26-7.36 (m, 2 H), 7.48-7.54 (d, J=5.2
Hz, 2 H). HPLC (method B): 94.5%, tR=13.2 min. MS (ESI)
468 m/z (M - Br)þ.
(3R)-3-{[Hydroxy(di-3-thienyl)acetyl]oxy}-1-(3-phenoxypro-
pyl)-1-azoniabicyclo[2.2.2]octane bromide (58) was prepared as
described for compound 43 starting from compound 23 (0.5 g,
1.43 mmol) and (3-bromopropoxy)benzene (0.46 g, 2.15
mmol). The reaction time was 6 h at reflux and 72 h at room
temperature. Trituration with diethyl ether gave 0.68 g (86%)
of compound 58, mp 219 °C. 1H NMR (300 MHz, DMSO-d6) δ
ppm 1.50-1.66 (m, 1 H), 1.66-1.82 (m, 1 H), 1.82-2.03 (m,
2 H), 2.03-2.24 (m, 2 H), 2.25-2.37 (m, 1 H), 3.08-3.25 (m,
1 H), 3.28-3.60 (m, 6 H), 3.86-4.02 (m, 1 H), 4.01-4.08 (t, J=
5.7 Hz, 2 H), 5.15-5.26 (m, 1 H), 6.78 (s, 1 H), 6.91-7.01 (m,
3 H), 7.11-7.17 (d, J=5.2 Hz, 2 H), 7.32 (m, 2 H), 7.42-7.48
(m, 2 H), 7.48-7.55 (m, 2 H). HPLC (method B): 99.7%, tR=
11.8 min. MS (ESI) 484 m/z (M - Br)þ.
(3R)-1-Benzyl-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-azonia-
bicyclo[2.2.2]octane bromide (53) was prepared as described for
compound 44 starting from compound 19 (0.20 g, 0.57 mmol)
and (bromomethyl)benzene (0.34 mL, 2.85 mmol). The reaction
time was 18 h. Trituration with diethyl ether gave 0.23 g (77%)
of compound 53, mp 89.0-90.6 °C (dec). 1H NMR (300 MHz,
DMSO-d6) δ ppm 1.57-2.03 (m, 4 H), 2.26 (m, 1 H), 2.98-3.15
(m, 1 H), 3.22-3.54 (m, 4 H), 3.81-3.94 (m, 1 H), 4.47 (d, J=
12.8 Hz, 1 H), 4.54 (d, J=12.8 Hz, 1 H), 5.21 (m, 1 H), 6.96 (dd,
J=8.6, 3.6 Hz, 2 H), 7.01-7.11 (d, J=3.1 Hz, 2 H), 7.44 (s, 1H),
7.45-7.61 (m, 7 H). HPLC (method B): 95.6%, tR=10.3 min.
MS (ESI) 440 m/z (M - Br)þ.
(3R)-3-[(2,2-Di-2-thienylpropanoyl)oxy]-1-(3-phenoxypro-
pyl)-1-azoniabicyclo[2.2.2]octane bromide (59) was prepared
as described for compound 44 starting from compound 26
(0.25 g, 0.72 mmol) and (3-bromopropoxy)benzene (0.77 g,
3.60 mmol). The reaction time was 72 h. Trituration with
diethyl ether gave 0.35 g (92%) of compound 59, mp 170 °C.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-2.25 (m, 6 H),
2.10 (s, 3 H), 2.25-2.34 (m, 1 H), 3.02-3.21 (m, 1 H), 3.30-
3.63 (m, 6 H), 3.90-4.08 (m, 1 H), 4.01-4.09 (t, J=5.5 Hz,
(3R)-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(2-phenylethyl)-
1-azoniabicyclo[2.2.2]octane bromide (54) was prepared as de-
scribed for compound 44 starting from compound 19 (0.20 g,
0.57 mmol) and (2-bromoethyl)benzene (0.53 g, 2.86 mmol).