K. Kusakabe et al. / Bioorg. Med. Chem. 21 (2013) 3154–3163
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trated. The residue was crystallized from EtOAc/hexane to give 17c
(220 mg, 88%) as a white solid. Mp 116 °C. 1H NMR (300 MHz,
CDCl3) d 1.00 (t, J = 7.5 Hz, 3H), 1.46 (sextet, J = 7.5 Hz, 2H), 1.68–
1.73 (m, 2H), 1.77 (quint, J = 6.0 Hz, 2H), 1.92 (quint, J = 6.0 Hz,
2H), 2.65 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 4.10 (t,
J = 7.8 Hz, 2H), 8.22 (s, 1H), 14.82 (s, 1H). Anal. calcd for
t, J = 6.0 Hz, 1H). Anal. calcd for C23H30N2O2: C, 75.37; H, 8.25; N,
7.64. Found: C, 75.39; H, 8.51; N, 7.58.
5.1.14. N-Benzyl-1-isopentyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (21a)
Compound 21a was prepared as described for 17c and 18c. 1H
NMR (300 MHz, CDCl3) d 0.99 (d, J = 6.7 Hz, 6H), 1.32–1.82 (m,
11H), 2.64 (t, J = 6.3 Hz, 2H), 2.87 (t, J = 6.3 Hz, 2H), 3.98–4.20 (br
s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 7.23–7.40 (m, 5H), 8.34 (s, 1H),
10.3 (br t, J = 6.0 Hz, 1H). HRMS-FAB (m/z): [M+H]+ calcd for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.19; H, 7.68;
N, 5.53.
5.1.9. N-Benzyl-1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-
3-carboxamide (18c)
C24H33N2O2, 381.2537; found: 381.2540.
To a solution of 17c (100 mg, 0.38 mmol) in toluene (3 mL) was
added thionyl chloride (83
l
L, 1.14 mmol), followed by DMF (one
5.1.15. N-Benzyl-1-(2-methoxyethyl)-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (21b)
drop). The mixture was heated to 75 °C and stirred for 30 min.
The mixture was allowed to cool to room temperature, and evapo-
rated. The mixture was diluted with CH2Cl2, and benzyl amine
Compound 21b was prepared as described for 17c and 18c. Mp
66 °C. 1H NMR (300 MHz, CDCl3) d 1.36 (quint, J = 6.0 Hz, 2H), 1.49
(quint, J = 6.0 Hz, 2H), 1.61–1.68 (m, 2H), 1.69 (quint, J = 6.0 Hz,
2H), 2.66 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 5.4 Hz, 2H), 4.32 (t,
J = 5.4 Hz, 2H), 4.64 (d, J = 6.0 Hz, 2H), 7.26–7.40 (m, 5H), 8.36 (s,
1H), 10.25 (br r, J = 6.0 Hz, 1H). HRMS-FAB (m/z): [M+H]+ calcd
(250 lL, 2.28 mmol) was added to this solution. The reaction mix-
ture was stirred for 30 min at room temperature, and poured onto
1 M HCl aqueous solution. The mixture was extracted with EtOAc,
and the combined organic extracts were washed with H2O, dried
over MgSO4, filtered and concentrated. The residue was purified
by flash column chromatography (silica gel, toluene/EtOAc = 6/1)
to give 18c (90 mg, 70%) as a white solid. 1H NMR (300 MHz, CDCl3)
d 0.97 (t, J = 7.5 Hz, 3H), 1.43 (sextet, J = 7.5 Hz, 2H), 1.62 (quint,
J = 7.5 Hz, 2H), 1.74 (quint, J = 6.0 Hz, 2H), 1.88 (quint, J = 6.0 Hz,
2H), 2.62 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 4.03 (t,
J = 7.8 Hz, 2H), 4.64 (d, J = 6.0 Hz, 2H), 7.23–7.38 (m, 5H), 8.28 (s,
1H), 10.32 (br t, J = 6.0 Hz, 1H). Anal. calcd for C21H26N2O2: C,
74.52; H, 7.74; N, 8.28. Found: C, 74.42; H, 7.73; N, 8.20.
for
C22H29N2O3, 369.2178; found: 369.2178. Anal. calcd for
C22H28N2O3: C, 71.71; H, 7.66; N, 7.60. Found: C, 71.54; H, 7.50;
N, 7.54.
5.1.16. N-Benzyl-1-(3-morpholinopropyl)-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (21c)
Compound 21c was prepared as described for 17c and 18c. 1H
NMR (300 MHz, CDCl3) d 1.34–1.54 (m, 4H), 1.60–1.81 (m, 4H),
1.82–1.94 (m, 2H), 2.28–2.50 (m, 6H), 2.64 (t, J = 6.4 Hz, 2H), 2.93
(t, J = 6.4 Hz, 2H), 3.70 (t, J = 4.5 Hz, 2H), 4.17 (t, J = 7.5 Hz, 2H),
4.17 (t, J = 7.5 Hz, 2H), 4.64 (d, J = 5.8 Hz, 2H), 7.20–7.39 (m, 5H),
8.34 (s, 1H). 10.29 (br t, 1H). HRMS-FAB (m/z): [M+H]+ calcd for
5.1.10. Methyl 1-butyl-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-
b]pyridine-3-carboxylate (16d)
Compound 16d was prepared in similar manner as 17c. 1H NMR
(300 MHz, CDCl3) d 0.97 (t, J = 7.3 Hz, 3H), 1.43 (dt, J = 14.9, 7.3 Hz,
2H), 1.62–1.73 (m, 2H), 2.81 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.98–
4.03 (m, 4H), 4.55 (s, 2H), 7.85 (s, 1H).
C26H36N3O3, 438.2751; found: 438.2755.
5.1.17. Butyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (22a)
Compound 22a was prepared in a similar manner as 18c after
substituting 17e for 17c. 1H NMR (300 MHz, CDCl3) d 0.99 (t,
J = 7.2 Hz, 3H), 1.37–1.56 (m, 4H), 1.47 (sextet, J = 7.2 Hz, 2H),
1.63–1.81 (m, 6H), 2.64 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H),
4.11 (t, J = 7.2 Hz, 2H), 5.69 (br s, 1H), 8.30 (s, 1H), 9.63 (br s,
1H). HRMS-FAB (m/z): [M+H]+ calcd for C16H25N2O2, 277.1905;
found: 277.1910.
5.1.11. N-Benzyl-1-butyl-2-oxo-2,5,7,8-tetrahydro-1H-
pyrano[4,3-b]pyridine-3-carboxamide (18d)
Compound 18d was prepared in a similar manner as 18c. 1H
NMR (300 MHz, CDCl3) d 0.98 (t, J = 7.5 Hz, 3H), 1.43 (sextet,
J = 7.5 Hz, 2H), 1.66 (quint, J = 7.5 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H),
4.01 (t, J = 6.0 Hz, 2H), 4.02 (t, J = 7.5 Hz, 2H), 4.60 (s, 2H), 4.64
(d, J = 6.0 Hz, 2H), 7.24–7.38 (m, 5H), 8.22 (s, 1H), 10.22 (br t,
J = 6.0 Hz, 1H). HRMS-FAB (m/z): [M+H]+ calcd for C20H25N2O3,
341.1860; found: 341.1866.
5.1.18. Butyl-N-isopropyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (22b)
Compound 22b was prepared in a similar manner as 18c after
substituting 17e for 17c. 1H NMR (300 MHz, CDCl3) d 0.99 (t,
J = 7.2 Hz, 3H), 1.26 (d, J = 6.9 Hz, 6H), 1.34–1.52 (m, 4H), 1.47 (sex-
tet, J = 7.2 Hz, 2H), 1.60–1.80 (m, 6H), 2.65 (t, J = 6.0 Hz, 2H), 2.88 (t,
J = 6.0 Hz, 2H), 4.09 (br t, J = 7.2 Hz, 2H), 4.25 (sextet, J = 6.6 Hz,
1H), 8.31 (s, 1H), 9.82 (br s, 1H). HRMS-FAB (m/z): [M+H]+ calcd
for C19H31N2O2, 319.238; found: 319.2384.
5.1.12. Butyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxylic acid (17e)
Compound 17e was prepared in a similar manner as 17c. Mp
110 °C. 1H NMR (300 MHz, CDCl3) d 1.00 (t, J = 7.3 Hz, 3H), 1.40–
1.50 (m, 6H), 1.66–1.73 (m, 4H), 1.76–1.84 (m, 2H), 2.67 (t,
J = 6.0 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 4.16 (t, J = 7.8 Hz, 2H), 8.28
(s, 1H). Anal. calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found:
C, 68.97; H, 8.49; N, 5.05.
5.1.19. Butyl-N-cyclohexyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (22c)
Compound 22c was prepared in a similar manner as 18c after
substituting 17e for 17c. Mp 90 °C. 1H NMR (300 MHz, CDCl3) d
0.99 (t, J = 7.2 Hz, 3H), 1.20–1.53 (m, 12H), 1.59–1.80 (m, 8H),
1.95–2.01 8 m, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H),
3.91–4.02 (m, 1H), 4.09 (br t, J = 7.2 Hz, 2H), 8.30 (s, 1H), 9.88 (d,
J = 7.5 Hz, 1H). HRMS-FAB (m/z): [M+H]+ calcd for C22H35N2O2,
359.2693; found: 359.2690.
5.1.13. N-Benzyl-1-butyl-2-oxo-1,2,5,6,7,8,9,10-
octahydrocycloocta[b]pyridine-3-carboxamide (18e)
Compound 18e was prepared in a similar manner as 18c. Mp
70 °C. 1H NMR (300 MHz, CDCl3) d 0.97 (t, J = 7.5 Hz, 3H), 1.35–
1.53 (m, 4H), 1.44 (sextet, J = 7.5 Hz, 2H), 1.60–1.78 (m, 6H), 2.64
(t, J = 6.0 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 4.09 (br t, J = 7.8 Hz, 2H),
4.64 (d, J = 6.0 Hz, 2H), 7.17–7.39 (m, 5H), 8.34 (s, 1H), 10.34 (br