H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
877
1
2.74–2.77 (m, 2H), 3.10–3.12 (m, 2H), 3.40 (brs, 2H),
3.61–3.64 (m, 2H), 3.68 (s, 3H), 3.71–3.73 (m, 9H),
3.96–3.97 (m, 2H), 4.54 (d, J=9.6 Hz, 2H), 6.42 (dd,
J=8.8, 2.8 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 6.74–6.78
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.11–2.16 (m, 2H), 2.25
(brs, 1H), 2.40–2.42 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.8 Hz, 2H), 3.12–3.14 (m, 2H), 3.40 (brs, 2H), 3.61–
3.67 (m, 2H), 3.71 (s, 6H), 4.11–4.14 (m, 2H), 4.54 (d,
J=8.3 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.6 Hz, 1H),
6.97 (dt, J=7.6, 1.1 Hz, 1H), 7.15 (dd, J=1.0 Hz, 1H),
7.33 (dt, J=7.8, 1.5 Hz, 1H), 7.40–7.45 (dd, J=7.8, 1.5
Hz, 1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd for
(m, 2H), 6.84 (d, J=8.8 Hz, 1H); MS (FAB) m/z=513
+
.
(M+H) . Anal. calcd for C29H40N2O6 C2H2O4: C,
61.78; H, 7.02; N, 4.65. Found: C, 61.60; H, 7.03; N, 4.65.
5.1.5. (Æ)-6,7-Dimethoxy-2-({1-[3-(2-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8c). Compound 8c was prepared from 5
and 7c in a manner similar to that described for com-
pound 8a with a yield of 75%. mp: 102–105 ꢀC (AcOEt–
.
.
C27H35N2O4Cl C2H2O4 0.1H2O: C, 60.17; H, 6.48; N,
4.84, Cl, 6.12. Found: C, 60.17; H, 6.19; N, 4.84; Cl, 6.03.
5.1.9. (Æ)-2-({1-[3-(3-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate hemi hydrate (8g). Compound 8g was pre-
pared from 5 and 7g in a manner similar to that descri-
bed for compound 8a with a yield of 55%. mp: 90–94 ꢀC
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.08–2.12 (m, 2H), 2.25
(brs, 1H), 2.41–2.47 (m, 2H), 2.61–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.13 (brs, 2H), 3.39 (brs, 2H), 3.41 (brs,
2H), 3.61–3.67 (m, 2H), 3.71 (s, 6H), 3.75 (s, 3H), 4.00–
4.02 (m, 2H), 4.54 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.78
(d, J=4.4 Hz, 1H), 6.87 (dd, J=7.6, 2.0 Hz, 1H), 6.90
(m, 3H), 6.90 (t, J=2.0 Hz, 1H), 6.93 (dd, J=7.2, 2.0 Hz,
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.16–1.19 (m, 1H), 1.66–1.80 (m, 3H), 2.08 (brs, 2H),
2.24 (brs, 1H), 2.39–2.43 (m, 2H), 2.59–2.68 (m, 2H),
2.76 (t, J=5.6 Hz, 2H), 3.11 (brs, 2H), 3.39 (brs, 2H),
3.61–3.64 (m, 2H), 3.71 (s, 6H), 4.05–4.08 (m, 2H), 4.54
(d, J=8.3 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.9 Hz, 1H),
6.90–6.94 (m, 1H), 6.98–7.04 (m, 2H), 7.32 (t, J=8.1
Hz, 1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd
1H), 6.97 (dt, J=7.6, 2.0 Hz, 1H); MS (FAB) m/z=483
+
.
.
(M+H) . Anal. calcd for C28H38N2O5 C2H2O4 0.6H2O:
C, 61.76; H, 7.12; N, 4.80. Found: C, 61.67; H, 6.99; N,
4.80.
.
.
for C27H35N2O4Cl C2H2O4 0.5H2O: C, 59.43; H, 6.54; N,
4.78, Cl, 6.05. Found: C, 59.43; H, 6.18; N, 4.71; Cl, 5.80.
5.1.6. (Æ)-6,7-Dimethoxy-2-({1-[3-(3-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8d). Compound 8d was prepared from 5
and 7d in a manner similar to that described for com-
pound 8a with a yield of 64%. mp: 88–93 ꢀC (AcOEt–
5.1.10. (Æ)-2-({1-[3-(4-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8h). Compound 8h was prepared from 5
and 7h in a manner similar to that described for com-
pound 8a with a yield of 81%. mp: 117–120 ꢀC (AcOEt–
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.08 (brs, 2H), 2.25 (brs,
1H), 2.39–2.47 (m, 2H), 2.61–2.68 (m, 2H), 2.76 (t,
J=6.0 Hz, 2H), 3.10–3.12 (m, 2H), 3.40 (brs, 2H), 3.61–
3.67 (m, 2H), 3.71(s, 6H), 3.73 (s, 3H), 4.00–4.03 (m,
2H), 4.54 (d, J=8.0 Hz, 2H), 6.48 (t, J=2.4 Hz, 1H),
6.51–6.54 (m, 2H), 6.74 (s, 1H), 6.78 (d, J=3.2 Hz, 1H),
7.18 (t, J=8.4 Hz, 1H); MS (FAB) m/z=483 (M+H)+.
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.18 (brs,
1H), 1.68–1.79 (m, 3H), 2.08–2.11 (m, 2H), 2.25 (brs,
1H), 2.39–2.43 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.09–3.11 (m, 2H), 3.39 (brs, 2H), 3.61–
3.64 (m, 2H), 3.71(s, 6H), 4.01–4.04 (m, 2H), 4.54 (d,
J=8.4 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.6 Hz, 1H),
6.96 (dt, J=8.8, 3.6 Hz, 1H), 7.33 (dt, J=8.4, 3.6 Hz,
1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd for
C27H35N2O4Cl C2H2O4 0.5H2O: C, 59.43; H, 6.54; N,
4.78, Cl, 6.05. Found: C, 59.33; H, 6.25; N, 4.77; Cl,
6.05.
.
.
Anal. calcd for C28H38N2O5 C2H2O4 0.8H2O: C, 61.38;
H, 7.14; N, 4.77. Found: C, 61.38; H, 7.15; N, 4.69.
.
.
5.1.7. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8e). Compound 8e was prepared from 5
and 7e in a manner similar to that described for com-
pound 8a with a yield of 76%. mp: 132–136 ꢀC (AcOEt–
5.1.11. (Æ)-2-({1-[3-(4-Fluorophenoxy)propyl]-3-piperi-
dyl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8i). Compound 8i was prepared from 5
and 7i in a manner similar to that described for com-
pound 8a with a yield of 81%. mp: 102–106 ꢀC (AcOEt–
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.18
(m, 1H), 1.67–1.80 (m, 3H), 2.06–2.08 (m, 2H), 2.24
(brs, 1H), 2.39–2.43 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.09–3.11 (m, 2H), 3.40 (brs, 2H), 3.61–
3.65 (m, 2H), 3.69 (s, 3H), 3.71(s, 6H), 3.95–3.98 (m,
2H), 4.54 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.78 (d,
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.18 (brs,
1H), 1.67–1.83 (m, 3H), 2.10–2.15 (m, 2H), 3.71 (s, 6H),
3.99–4.00 (m, 2H), 4.54 (d, J=8.0 Hz, 2H), 6.74 (s, 1H),
6.78 (d, J=3.6 Hz, 1H), 6.92–6.97 (m, 2H), 7.09–7.14
(m, 2H); MS (FAB) m/z=471(M+H) +. Anal. calcd
for C27H35N2O4F C2H2O4 0.6H2O: C, 60.96; H, 6.74;
N, 4.90, F, 3.32. Found: C, 60.90; H, 6.61; N, 4.73; F,
3.42.
J=3.6 Hz, 1H), 6.86 (s, 4H); MS (FAB) m/z=483
+
.
.
(M+H) . Anal. calcd for C28H38N2O5 C2H2O4 0.8H2O:
C, 61.38; H, 7.14; N, 4.77. Found: C, 61.35; H, 7.05; N,
4.67.
.
.
5.1.8. (Æ)-2-({1-[3-(2-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8f). Compound 8f was prepared from 5
and 7f in a manner similar to that described for com-
pound 8a with a yield of 48%. mp: 156–158 ꢀC (AcOEt–
5.1.12. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-methylphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8j). Compound 8j was prepared from 5
and 7j in a manner similar to that described for