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R. Palin et al. / Bioorg. Med. Chem. 15 (2007) 1828–1847
J = 3.85, 12.05 Hz, 1H), 4.36 (dd, J = 5.3, 10.6 Hz, 1H),
4.11 (t, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.77–3.69 (m, 2H),
3.35-3.16 (m, 5H), 2.87–2.75 (m, 2H), 2.85 (t, J = 6.8 Hz,
2H), 2.20–2.04 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.03
(dd, J = 6.8, 14.5 Hz, 6H).
the title compound as a white solid in 69% yield. ESI-
MS m/z = 514.3 (M+H)+. 1H NMR (400 MHz, CDCl3):
d 7.34-7.28 (m, 2H), 7.13–7.11 (m, 2H), 7.02 (d,
J = 8.3 Hz, 1H), 6.63 (s, 1H), 6.36 (dd, J = 2.4, 8.2 Hz,
1H), 5.09 (d, J = 13.5 Hz, 1H), 4.87 (d, J = 13.5 Hz,
1H), 4.36 (tt, J = 4.3, 8.3 Hz, 1H), 4.25-4.23 (m, 1H),
3.76 (s, 3H), 3.09 (d, J = 10.6 Hz, 1H), 2.97 (d,
J = 10.6 Hz, 1H), 2.67 (s, 3H), 2.50–2.42 (m, 4H), 2.16
(s, 3H), 2.12–1.97 (m, 3H), 1.85–1.75 (m, 4H), 1.56 (s,
3H), 0.98 (dd, J = 6.9, 9.1 Hz, 6H).
4.1.45. 1-(2-Dimethylamino-ethyl)-3-{1-[3-(5-methoxy-2-
methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-
dihydro-benzimidazol-2-one (7m). Flash chromatography
on silica gel (ethyl acetate/triethylamine; 9:1; as eluant)
gave the product as an oil in 62 % yield. ESI-MS
1
m/z = 509.4 (M+H)+. H NMR (400 MHz, CDCl3): d
4.1.49. 1-Methanesulfonylmethyl-3-{1-[3-(5-methoxy-2-
methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-
dihydro-benzimidazol-2-one methanesulfonate (7s). Flash
chromatography on silica gel (dichloromethane/metha-
nol; 100:0–98:2; gradient elution) gave the title com-
pound as the free base. Dissolving the compound in
dichloromethane and adding one equivalent of methane-
sulfonic acid prepared the methane sulfonate salt. The
solution was then evaporated and acetone/diethyl ether
added to form a precipitate, which was collected by fil-
tration and dried to give the title compound as a white
solid in 45% yield. ESI-MS m/z = 530.2 (M+H)+. 1H
NMR (400 MHz, CDCl3): d 7.36–7.34 (m, 1H), 7.28–
7.24 (m, 1H), 7.16–7.13 (m, 2H) 7.02 (d, J = 8.2 Hz,
1H), 6.63 (s, 1H), 6.39–6.36 (m, 1H), 5.06 (s, 2H),
4.36–4.31 (m, 1H), 4.29–4.23 (m, 1H), 3.76 (s, 3H),
3.10 (d, J = 11.0 Hz, 1H), 2.98 (s, 3H), 3.00–2.97 (m,
1H), 2.51–2.40 (m, 4H), 2.16 (s, 3H), 2.14–1.62 (m,
7H), 0.98 (dd, J = 7.3, 9.3 Hz, 6H).
7.34–7.28 (m, 1H), 7.10–7.00 (m, 4H), 6.62 (d,
J = 2.4 Hz, 1H), 6.36 (dd, J = 2.4, 8.2 Hz, 1H), 4.38
(tt, J = 4.2, 12.5 Hz, 1H), 4.24 (dd, J = 4.8, 11.5 Hz,
1H), 3.98 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.67 (s,
3H), 3.08 (d, J = 11.8 Hz, 1H), 2.97 (d, J = 12.5 Hz,
1H), 2.63 (t, J = 7.3 Hz, 2H), 2.52–2.34 (m, 4H), 2.33
(s, 6H), 2.18–1.96 (m, 3H), 2.16 (s, 3H), 1.88–1.72 (m,
4H), 0.98 (dd, J = 6.8, 9.0 Hz, 6H).
4.1.46.
1-[2-(Benzyl-methyl-amino)-ethyl]-3-{1-[3-(5-
methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-
4-yl}-1,3-dihydro-benzimidazol-2-one (7n). Flash chro-
matography on silica gel (dichloromethane/methanol;
98:2; as eluant) gave the product as an oil in 46% yield.
ESI-MS m/z = 585.2 (M+H)+. 1H NMR (400 MHz,
CDCl3): d 7.30 (d, J = 7.3 Hz, 1H), 7.24–7.15 (m, 5H),
7.06–6.96 (m, 3H), 6.87–6.83 (m, 1H), 6.62 (d, J = 2.4
Hz, 1H), 6.36 (dd, J = 2.4, 8.2 Hz, 1H), 4.38 (tt,
J = 4.2, 12.5 Hz, 1H), 4.24 (dd, J = 4.8, 11.5 Hz, 1H),
3.98 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.55 (s, 2H), 3.08
(d, J = 11.7 Hz, 1H), 2.97 (d, J = 11.7 Hz, 1H), 2.71 (t,
J = 7.0 Hz, 2H), 2.52–2.36 (m, 4H), 2.35 (s, 3H), 2.18–
1.96 (m, 3H), 2.16 (s, 3H), 1.88–1.72 (m, 4H), 0.98
(dd, J = 6.8, 9.0 Hz, 6H).
4.1.50.
1-Ethoxymethyl-3-{1-[3-(5-methoxy-2-methyl-
phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-dihydro-
benzimidazol-2-one (7c). Trifluoroacetic acid (20 mL)
was added to a magnetically stirred solution of 3c
(4.0 g, 10.7 mmol) in dichloromethane (120 mL). The
reaction mixture was left to stir for 3 h at room temper-
ature then neutralised with aqueous sodium carbonate
solution and the organic layer collected. The organics
were then washed with water and brine before drying
over Na2SO4, filtering and concentrating under reduced
pressure to give the intermediate amine as a colourless
solid. The amine, 4c, was then used without further puri-
fication in a similar manner to the procedure outlined
for 7f obtaining the title compound as a colourless solid
4.1.47. 3-(3-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-
pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzimidazol-1-
yl)-N-methyl-propionamide (7o). Flash chromatography
on silica gel (dichloromethane/methanol; 98:2; as elu-
ant) gave the product as an oil in 32% yield. ESI-MS
1
m/z = 523.0 (M+H)+. H NMR (400 MHz, CDCl3): d
7.33 (d, J = 6.9 Hz, 1H), 7.16–7.04 (m, 3H), 7.02 (d,
J = 8.7 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1 H), 6.37 (dd,
J = 2.4, 8.2 Hz, 1H), 6.26 (br d, J = 3.9 Hz, 1H), 4.36
(tt, J = 4.2, 12.5 Hz, 1H), 4.23 (dd, J = 4.6, 11.6 Hz,
1H), 4.19 (t, J = 6.7 Hz, 2H), 3.76 (s, 3 H), 3.09
(d, J = 11.7 Hz, 1H), 2.99 (d, J = 11.5 Hz, 1H), 2.76
(d, J = 4.7 Hz, 3H), 2.67 (t, J = 6.7 Hz, 2H), 2.54–2.36
(m, 4H), 2.18–1.96 (m, 3H), 2.16 (s, 3H), 1.88–1.68
(m, 4H), 0.98 (dd, J = 6.8, 9.0 Hz, 6H).
1
in 65% yield. ESI-MS m/z = 496.5 (M+H+). H NMR
(400 MHz, CDCl3): d 7.36–7.31 (m, 1H), 7.22–7.17 (m,
1H), 7.13–7.07 (m, 2H) 7.02 (d, J = 8.2 Hz, 1H), 6.62
(d, J = 2.3 Hz, 1H), 6.36 (dd, J = 2.4, 8.2 Hz, 1H), 5.33
(s, 2H), 4.39 (tt, J = 4.3, 13.0 Hz, 1H), 4.25–4.21 (m,
1H), 3.76 (s, 3H), 3.58 (q, J = 7.0 Hz, 2H), 3.09 (d,
J = 11.5 Hz, 1H), 2.98 (d, J = 11.5 Hz, 1H), 2.53–2.37
(m, 4H), 2.15 (s, 3H), 2.14–1.97 (m, 3H), 1.87-1.76 (m,
4H), 1.18 (t, J = 7.0 Hz, 3H), 0.98 (dd, J = 6.8, 9.7 Hz,
6H).
4.1.48. 1-Methanesulfinylmethyl-3-{1-[3-(5-methoxy-2-
methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-
dihydro-benzimidazol-2-one methanesulfonate (7r). Flash
chromatography on silica gel (dichloromethane/metha-
nol; 98:2; as eluant) gave the title compound as the free
base. Dissolving the compound in dichloromethane and
adding one equivalent of methanesulfonic acid prepared
the methane sulfonate salt. The solution was then evap-
orated and acetone/diethyl ether added to form a precip-
itate, which was collected by filtration and dried to give
4.1.51. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-
pentyl]-piperidin-4-yl}-3-(2-oxo-butyl)-1,3-dihydro-benzimi-
dazol-2-one methanesulfonate (7d). Trifluoroacetic acid
(1.6 mL) was added to a magnetically stirred solution
of 3d (800 mg, 2.1 mmol) in dichloromethane (16 mL).
The reaction mixture was left to stir for 3 h at room
temperature. The mixture was then evaporated to a