S. Kasai et al. / Bioorg. Med. Chem. 19 (2011) 6261–6273
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was extracted with AcOEt (20 mL ꢂ 2). The extract was washed
with water (20 mL) and brine (20 mL), dried over MgSO4. After re-
moval of the solvent under reduced pressure, the resulting pale
yellow solid was triturated with Et2O/diisopropyl ether solution
to yield 2f (0.22 g, 76%) as a colorless powder: mp 110–112 °C.
1H NMR (300 MHz, CDCl3) d: 1.19 (3H, t, J = 7.5 Hz), 1.62–1.80
(4H, m), 1.95–2.08 (4H, m), 2.41–2.48 (5H, m), 2.97–3.04 (8H,
m), 3.59–3.61 (2H, m), 3.73–3.76 (2H, m), 7.12 (2H, d, J = 8.1 Hz),
7.20–7.26 (3H, m), 7.56–7.78 (2H, m). Anal. (C28H35Cl N2O2) C, H, N.
m), 3.43––3.47 (4H, m), 7.12 (2H, d, J = 8.4 Hz), 7.22–7.26 (3H, m),
7.77–7.81 (2H, m). Anal. (C26H33ClN2O3Sꢁ0.5H2O) C, H, N.
7.17. 4-[4-(4-Chlorophenyl)piperidin-1-yl]-1-[3-(ethylsulfonyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]butan-1-one (2l)
The title compound was prepared by a procedure similar to
the one described for 2k to provide 2l (58%) as a colorless solid:
mp 138–139 °C. 1H NMR (300 MHz, CDCl3) d: 1.33 (3H, t,
J = 7.4 Hz), 1.59–1.74 (4H, m), 1.94–2.09 (4H, m), 2.44 (3H, t like),
2.92–3.11 (10H, m), 3.46–3.50 (4H, m), 7.11 (2H, d, J = 8.8 Hz),
7.21–7.27 (3H, m), 7.76–7.80 (2H, m). Anal. (C27H35ClN2O3S) C,
H, N.
7.12. 1-(3-Butyryl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-
[4-(4-chlorophenyl)piperidin-1-yl]-butan-1-one (2g)
The title compound was prepared by a procedure similar to
the one described for 2f to provide 2g (54%) as a colorless pow-
der: mp 93–94 °C. 1H NMR (300 MHz, CDCl3) d: 0.99 (3H, t,
J = 7.5 Hz), 1.62–1.80 (6H, m), 1.95–2.07 (4H, m), 2.37–2.46 (5H,
m), 2.95–3.04 (8H, m), 3.60–3.61 (2H, m), 3.73–3.75 (2H, m),
7.12 (2H, d, J = 8.1 Hz), 7.20–7.26 (3H, m), 7.76–7.78 (2H, m).
Anal. (C29H37Cl N2O2) C, H, N.
7.18. Methyl-7-{4-[4-(4-chlorophenyl)piperidin-1-yl]butanoyl}-
1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (2m)
A mixture of 1b (0.20 g, 0.41 mmol) in AcOEt (20 mL) was
washed with 2 M NaOH (20 mL) and brine (20 mL), dried over
anhydrous MgSO4. After removal of the solvent under reduced
pressure, the resulting residue was dissolved in THF (10 mL). To
this solution was added triethylamine (0.070 mL, 0.50 mmol) and
methyl chlorocarbonate (0.050 g, 0.50 mmol) successively. After
being stirred at room temperature for 16 h, the reaction mixture
was poured into water (40 mL) and the mixture was extracted with
AcOEt (20 mL ꢂ 2). The extract was washed with brine and dried
over anhydrous MgSO4. After removal of the solvent under reduced
pressure, the resulting residue was purified by alumina column
chromatography (hexane/AcOEt = 1/1) to give 2m (0.14 g, 73%) as
a colorless oil. This oil was treated with 4 M HCl (AcOEt solution)
to give a colorless solid: mp 61 °C. 1H NMR (300 MHz, CDCl3, free
amine) d: 1.66–1.80 (4H, m), 1.95–2.07 (6H, m), 2.34 (2H, t,
J = 7.2 Hz), 2.96–3.04 (7H, m), 3.61 (4H, br s), 3.75 (3H, s), 7.11
(2H, d, J = 8.7 Hz), 7.20–7.27 (3H, m), 7.75–7.77 (2H, m). Anal.
(C27H33Cl N2O3ꢁHCl) C, H, N.
7.13. 4-[4-(4-Chlorophenyl)piperidin-1-yl]-1-[3-(cyclopropylcar
bonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]butan-1-one
(2h)
The title compound was prepared by a procedure similar to the
one described for 2f to provide 2h (57%) as a white solid: mp 122–
124 °C. 1H NMR (300 MHz, CDCl3) d: 0.77–0.84 (2H, m), 1.00–1.04
(2H, m), 1.62–1.86 (4H, m), 1.93–2.07 (6H, m), 2.42–2.47 (1H, m),
2.44 (2H, t, J = 7.2 Hz), 2.97–3.04 (7H, m), 3.75–3.81 (4H, m), 7.12
(2H, d, J = 8.4 Hz), 7.23–7.26 (3H, m), 7.76–7.78 (2H, m). Anal.
(C29H35Cl N2O2) C, H, N.
7.14. 4-[4-(4-Chlorophenyl)piperidin-1-yl]-1-(3-pentanoyl-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-butan-1-one (2i)
The title compound was prepared by a procedure similar to the
one described for 2f to provide 2i (59%) as a pale red solid: mp
88 °C (decomp.). 1H NMR (300 MHz, CDCl3) d: 0.94 (3H, t,
J = 7.5 Hz), 1.39 (2H, sext, J = 7.5 Hz), 1.60–1.80 (6H, m), 1.95–
2.08 (4H, m), 2.39–2.46 (5H, m), 2.95–3.04 (8H, m), 3.60–3.61
(2H, m), 3.72–3.75 (2H, m), 7.12 (2H, d, J = 8.1 Hz), 7.20–7.26
(3H, m), 7.76–7.79 (2H, m). Anal. (C30H39Cl N2O2) C, H, N.
7.19. 7-{4-[4-(4-Chlorophenyl)piperidin-1-yl]butanoyl}-N-eth
yl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide (2n)
The title compound was prepared by a procedure similar to the
one described for 2f to provide 2n (94%) as a colorless solid. This
solid was triturated with diisopropyl ether to give a colorless pow-
der: mp 146–148 °C. 1H NMR (200 MHz, CDCl3) d: 1.17 (3H, t,
J = 7.4 Hz), 1.76 (4H, br m), 1.99–2.02 (4H, br m), 2.44–2.47 (2H,
m), 3.00–3.03 (9H, m), 3.32 (2H, m), 3.55 (4H, m), 4.47 (1H, m),
7.12 (2H, d, J = 8.4 Hz), 7.19–7.26 (3H, m), 7.74–7.77 (2H, m). Anal.
(C28H36 Cl N3O2ꢁ0.3H2O) C, H, N.
7.15. 1-(3-Benzoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-
[4-(4-chlorophenyl)piperidin-1-yl]-butan-1-one (2j)
The title compound was prepared by a procedure similar to the
one described for 2f to provide 2j (94%) as a colorless powder: mp
103–105 °C. 1H NMR (200 MHz, CDCl3) d: 1.65–1.80 (6H, m), 1.93–
2.08 (6H, m), 2.44 (2H, t like), 2.95–3.11 (5H, m), 3.52 (2H, br m),
3.89 (2H, br s), 7.09–7.46 (10H, m), 7.77–7.80 (2H, m). Anal.
(C30H35Cl N2O2) C, H, N.
7.20. 1-(2-Acetyl-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)-4-
chlorobutan-1-one (15)
The title compound was prepared by a procedure similar to the
one described for 6 to provide 15 (62%) as a colorless solid. 1H NMR
(200 MHz, CDCl3) d: 1.76–1.90 (2H, m), 2.05 and 2.12 (3H, s), 2.14–
2.27 (2H, m), 2.94–3.06 (2H, m), 3.00–3.17 (2H, m), 3.63–3.77 (2H,
m), 3.70–3.86 (2H, br m), 4.56 and 4.61 (2H, s), 7.13–7.39 (2H, m),
7.77–7.97 (1H, m).
7.16. 4-[4-(4-Chlorophenyl)piperidin-1-yl]-1-[3-(methylsulfo
nyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]butan-1-one (2k)
A mixture of 1b (0.15 g, 0.34 mmol), methanesulfonyl chloride
(0.05 g, 0.41 mmol) and triethylamine (0.16 mL, 1.12 mmol) in
THF (10 mL) was stirred at room temperature for 2 h. The reaction
mixture was poured into 5% NaHCO3 (50 mL) and the mixture was
extracted with AcOEt (30 mL ꢂ 2). The extract was washed with
water and brine, dried over MgSO4. After removal of the solvent un-
der reduced pressure, 2k (0.15 g, 90%) was obtained as a pale yellow
solid: mp 156–158 °C. 1H NMR (200 MHz, CDCl3) d: 1.64–1.75 (4H,
m), 1.95–2.14 (4H, m), 2.47 (2H, t like), 2.79 (3H, s), 2.97–3.13 (9H,
7.21. 1-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-
chlorobutan-1-one (16)
The title compound was prepared by a procedure similar to the
one described for 6 to provide 16 (68%) as colorless crystals. 1H
NMR (300 MHz, CDCl3) d: 2.19 (3H, s), 2.25 (2H, m), 2.95 (2H, m),
3.17 (2H, quint, J = 6.9 Hz), 3.68 (3H, m), 3.85 (1H, t, J = 6.3 Hz),
4.71 (2H, s), 7.25 (1H, m), 7.78 (2H, m).