8
S. Nagashima et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
4.1.23. (3R)-1-Azabicyclo[2.2.2]oct-3-yl (2-phenyl-3-thienyl)
carbamate hydrochloride (28)
9.72 (1H, br), 10.62 (1H, br); FAB MS m/e [M+H]+ 398; HRMS calcd
for C18H18N3F3O2S [M+H]+ 398.1150, found 398.1150.
Yield: 49%, colorless amorphous solid. 1H NMR (DMSO-d6) d
1.79–1.90 (3H, m), 2.00 (1H, br), 2.23 (1H, br), 3.12–3.20 (5H, m),
3.60 (1H, br), 4.87 (1H, br), 7.15 (1H, d, J = 5.2 Hz), 7.32–7.36 (1H,
m), 7.42–7.46 (2H, m), 7.51–7.55 (3H, m), 9.25(1H, br), 10.23
(1H, br); 13C NMR (100 MHz, DMSO-d6) d 17.43, 20.64, 24.73,
45.51, 46.29, 53.43, 68.21, 124.51, 128.53, 128.60, 129.82, 132.07,
133.72; FAB MS m/e [M+H]+ 329; HRMS calcd for C18H20N2O2S
[M+H]+ 329.1324, found 329.1330; Anal. Calcd for C18H20N2O2S
4.1.30. (3R)-1-Azabicyclo[2.2.2]oct-3-yl (4-phenyl-1,3-thiazol-5-
yl)carbamate hydrochloride (37)
Yield: 8%, pale-brown solid. 1H NMR (DMSO-d6) d 1.80 (3H, br),
2.05 (1H, br), 2.29 (1H, br s), 3.16–3.23 (5H, m), 3.64 (1H, br s), 4.97
(1H, br s), 7.37 (1H, t, J = 7.4 Hz), 7.47 (2H, t, J = 7.7 Hz), 7.78 (2H, d,
J = 7.4 Hz), 8.92 (1H, s), 10.92 (1H, br), 10.4 (1H, br); FAB MS m/e
[M+H]+ 330. mp: 147–148 °C, [
a]
À10.8°(c 0.12, MeOH); HRMS
26
D
HCl 1.5H2O 0.1C4H8O2: C, 55.15; H, 6.24; N, 6.99; S, 8.00; Cl,
calcd for C17H19N3O2S [M+H]+ 330.1276, found 330.1275.
26
8.85. Found: C, 55.42; H, 6.20; N, 6.81; S, 7.03; Cl, 8.55; [a]
D
À5.3 (c 0.2, MeOH).
4.1.31. (3R)-1-Azabicyclo[2.2.2]oct-3-yl (5-phenyl-1,3-oxazol-4-
yl)carbamate hydrochloride (38)
4.1.24. (3S)-1-Azabicyclo[2.2.2]oct-3-yl (2-phenyl-3-thienyl)
carbamate hydrochloride (29)
Yield: 6%, pale-yellow amorphous solid. 1H NMR (DMSO-d6) d
1.81–1.87 (4H, m), 2.24 (1H, br s), 3.14 (5H, br s), 3.64 (1H, br s),
4.91 (1H, br s), 7.4 (1H, t, J = 7.6 Hz), 7.5 (2H, t, J = 7.6 Hz), 7.67
Yield: 20%, colorless amorphous solid. 1H NMR (DMSO-d6) d
1.79–1.90 (3H, m), 2.00 (1H, br), 2.23 (1H, br), 3.12–3.20 (5H, m),
3.60 (1H, br), 4.87 (1H, br), 7.15 (1H, d, J = 5.2 Hz), 7.32–7.36 (1H,
m), 7.42–7.46 (2H, m), 7.51–7.55 (3H, m), 9.26 (1H, br), 10.55 (1H,
br); 13C NMR (100 MHz, DMSO-d6) d 17.43, 20.64, 24.73, 45.51,
46.29, 53.43, 68.20, 124.51, 128.53, 128.60, 129.81, 132.07,
133.71; FAB MS m/e [M+H]+ 329; Anal. HRMS calcd for C18H20N2O2S
[M+H]+ 329.1324, found 329.1330; calcd for C18H20N2O2S HCl H2O
0.1C4H8O2: C, 56.42; H, 6.12; N, 7.15; S, 8.19; Cl, 9.05. Found: C,
(2H, d, J = 7.6 Hz), 8.4 (1H, s), 9.62 (1H, br s), 9.87 (1H, br s); FAB
MS m/e [M+H]+ 314, [
C
a
]
D
À5.7 (c 0.07, MeOH); HRMS calcd for
26
17H19N3O3 [M+H]+ 314.1505, found 314.1504.
4.1.32. 1-Azabicyclo[2.2.2]oct-4-yl [5-(3,5-dichlorophenyl)-1,3-
thiazol-4-yl]carbamate fumarate (36)
Free base of 36 was prepared using an approach similar to that
described for 25 to give a colorless amorphous solid (yield: 21%).
To a mixture of the free amine of 36 (45 mg, 0.113 mmol) in MeOH
(2 mL) was added fumaric acid (13 mg), and the mixture was con-
centrated in vacuo. The resulting residue was triturated with EtOH
to give 36 (51 mg) as a colorless amorphous solid. 1H NMR (DMSO-
d6) d 1.87–1.91 (6H, br), 2.94–2.98 (6H, br), 8.52 (1.5H, s, fumaric
acid), 7.54 (2H, d, J = 2.0 Hz), 7.64 (1H, t, J = 2.0 Hz), 9.06 (1H, s),
9.55 (1H, br); 13C NMR (100 MHz, DMSO-d6) d 30.18, 48.44,
77.27, 125.68, 127.01, 128.32, 135.34, 135.39, 144.73, 152.99,
153.63, 168.28; FAB MS m/e [M+H]+ 398; HRMS calcd for C17H17N3-
O2Cl2S [M+H]+ 398.0497, found 398.0503.
56.61; H, 6.28; N, 7.06; S, 7.47; Cl, 8.75; [a]
26 +6.3 (c 0.23, MeOH).
D
4.1.25. (3R)-1-Azabicyclo[2.2.2]oct-3-yl (5-phenyl-1,3-thiazol-4-
yl)carbamate hydrochloride (31)
Yield: 14%, pale-yellow amorphous solid. 1H NMR (DMSO-d6) d
1.72–1.91 (4H, m), 2.14 (1H, br s), 2.93–3.21 (5H, m), 3.56–3.61
(1H, m), 4.83–4.85 (1H, m), 7.39 (1H, t, J = 7.3 Hz), 7.46 (2H, t,
J = 7.6 Hz), 7.56 (2H, d, J = 7.4 Hz), 9.02 (1H, s), 9.65 (1H, br),
10.21 (1H, br); FAB MS m/e [M+H]+ 330; HRMS calcd for C17H19N3-
O2S [M+H]+ 330.1276, found 330.1284; [
a]
À7.0 (c 0.1, MeOH).
26
D
4.1.26. 1-Azabicyclo[2.2.2]oct-4-yl [5-(3-chlorophenyl)-1,3-
thiazol-4-yl]carbamate hydrochloride (32)
4.1.33. 1-Methyl-4-{[(5-phenyl-1,3-thiazol-4-yl)carbamoyl]
oxy}-1-azoniabicyclo[2.2.2]octane iodide (40)
Yield: 19%, pale-brown amorphous solid. 1H NMR (DMSO-d6) d
2.17 (6H, br s), 3.34–3.39 (6H, m), 7.44–7.49 (3H, m), 7.58–7.58
(1H, m), 9.04 (1H, s), 9.64 (1H, br), 10.2 (1H, br); FAB MS m/e
[M+H]+ 364.
To a solution of 30 (100 mg, 0.304 mmol) in CHCl3 (3 mL) was
added iodomethane (0.076 mL, 1.22 mmol) at room temperature
and stirred. After 1 h, iodomethane (0.076 mL, 1.22 mmol) was
added to the mixture and stirred for a further 1 h. A solid precipi-
tated during stirring, and after the reaction mixture was diluted
with AcOEt, the resulting precipitate was collected via filtration
and washed with AcOEt to produce the desired compound 40
(133 mg, 93 %) as a pale-yellow solid. 1H NMR (DMSO-d6) d 2.15–
2.30 (6H, m), 2.92 (3H, s), 3.56–3.63 (6H, m), 7.36–7.41 (1H, m),
7.44–7.48 (2H, m), 7.51–7.54 (2H, m), 9.00 (1H, s), 9.53 (1H, br);
4.1.27. (3R)-1-azabicyclo[2.2.2]oct-3-yl [5-(3-chlorophenyl)-1,3-
thiazol-4-yl]carbamate hydrochloride (33)
Yield: 49%, pale-brown amorphous solid. 1H NMR (DMSO-d6)
d1.73–1.91 (4H, m), 2.16 (1H, br), 2.93–3.23 (5H, m), 3.57–3.63
(1H, m), 4.85–4.87 (1H, m), 7.44–7.51 (3H, m), 7.61 (1H, br), 9.07
(1H, s), 9.79 (1H, br s), 10.47 (1H, br); 13C NMR (100 MHz, DMSO-
d6) d 17.37, 20.55, 24.75, 45.53, 46.34, 53.27, 68.46, 127.65,
127.86, 128.05, 129.03, 131.80, 133.49, 134.49, 143.63, 152.51,
13C NMR (100 MHz, DMSO-d6)
d 28.74, 51.91, 57.88, 73.61,
128.66, 129.14, 129.86, 131.48, 142.90, 151.60, 153.64; FAB MS
m/e [M]+ 344; HRMS calcd for C18H22N3O2S [M]+ 344.1433, found
154.49; FAB MS m/e [M+H]+ 364; HRMS calcd for C17H18N3ClO2S
344.1428; Anal. Calcd for
C18H22N3O2S.I.0.7H2O.0.1C4H8O2: C,
[M+H]+ 364.0887, found 364.0886; [
a]
À5.0 (c 0.02, MeOH).
26
D
44.85; H, 4.95; N, 8.53; S, 6.51; I, 25.75. Found: C, 44.84; H, 4.71;
N, 8.73; S, 6.61; I, 25.79, mp: 194–195 °C.
4.1.28. 1-Azabicyclo[2.2.2]oct-4-yl [5-(4-fluorophenyl)-1,3-
thiazol-4-yl]carbamate hydrochloride (34)
4.1.34. 1-Methyl-4-{[(2-phenyl-3-thienyl)carbamoyl]oxy}-1-
azoniabicyclo[2.2.2]octane iodide (39)
Yield: 12%, colorless amorphous solid. 1H NMR (DMSO-d6) d 2.14
(6H, br s), 3.35–3.37 (6H, br), 7.28–7.34 (2H, m), 7.53–7.58 (2H, m),
8.99 (1H, s), 9.51 (1H, br), 10.35 (1H, br); FAB MS m/e [M+H]+ 348,
HRMS calcd for C17H18N3FO2S [M+H]+ 348.1182, found 348.1187.
Compound 39 was prepared from free base of 27 using an
approach similar to that described for compound 40. Yield: 97%,
colorless amorphous solid. 1H NMR (DMSO-d6) d 2.32 (6H, br),
2.93 (3H, br), 3.61 (6H, br), 7.05 (1H, br), 7.34 (1H, t, J = 7.3 Hz),
7.44 (2H, t, J = 7.6 Hz), 7.49–7.51 (2H, m), 9.14 (1H, br); 13C NMR
(100 MHz, DMSO-d6) d 28.85, 51.94, 57.93, 73.43, 124.48, 128.49,
129.75, 131.93, 133.03; FAB MS m/e [M]+ 343; HRMS calcd for
4.1.29. 1-Azabicyclo[2.2.2]oct-4-yl {5-[3-(trifluoromethyl)
phenyl]-1,3-thiazol-4-yl}carbamate hydrochloride (35)
Yield: 21%, pale-brown amorphous solid. 1H NMR (DMSO-d6) d
2.14 (6H, br s), 3.35–3.43 (6H, br), 7.68–7.84 (4H, m), 9.08 (1H, s),
C
19H23N2O2S [M]+ 343.1480, found 343.1488; Anal. Calcd for