J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 6430–6446
6441
HCl–EtOAc (0.45 mL) and triturated with Et2O to provide 13 (0.74 g,
99%) as white powder. Mp 200–202 °C; 1H NMR (CDCl3) d: 1.77–
1.95 (1H, m), 2.24–2.36 (1H, m), 2.71 (1H, dt, J = 10.6, 3.6 Hz),
2.82–3.10 (3H, m), 3.34–3.60 (6H, m), 3.72 (1H, d, J = 13.8 Hz),
5.00–6.60 (2H, br), 6.87 (1H, d, J = 2.4 Hz), 7.02–7.10 (3H, m),
7.24–7.34 (3H, m). The NMR spectrum was measured as a free base,
and the amino NH signal was not observed; ESI-MS m/z 381
[(MꢁHCl+H)+]; Anal. Calcd for C20H24ClN2O2F3: C, 57.62; H, 5.80;
N, 6.72. Found: C, 57.38; H, 5.82; N, 6.63.
the reaction mixture was poured into H2O, and then the mixture
was extracted with EtOAc. The extract was washed with aqueous
NH4Cl and brine, dried and concentrated. The residue was purified
by preparative HPLC to give an oil, which was treated with 1 equiv
of 4 N HCl–EtOAc (0.10 mL) to provide 17 as white amorphous. 1H
NMR (CDCl3) d: 1.60–1.80 (1H, m), 1.90–2.05 (1H, m), 2.05–2.14
(3H, m), 2.90–3.05 (2H, m), 3.25–3.98 (9H, m), 4.20–4.59 (1H,
m), 6.64 (1H, dd, J = 8.7, 5.1 Hz), 6.89 (1H, s like), 6.98–7.15 (3H,
m), 7.20–7.35 (3H, m). The NMR spectrum was measured as a free
base; ESI-MS m/z 423 [(MꢁHCl+H)+]; chemical purity: 96.5%.
5.1.11. cis-1-Ethyl-N-[2-methoxy-5-(trifluoromethoxy)benzyl]-
3-phenyl-4-piperidinamine hydrochloride (14)
5.1.15. cis-N-Ethyl-4-{[2-methoxy-5-(trifluoromethoxy)benzyl]
amino}-3-phenylpiperidine-1-carboxamide (18)
A solution of 12 (0.23 g, 0.50 mmol) ethyl iodide (0.083 g,
0.53 mmol) and Et3N (0.10 g, 1.0 mmol) in THF (5 mL) and DMF
(1 mL) was stirred at room temperature for 3 h. The reaction mix-
ture was poured into H2O and extracted with EtOAc. The extract
was washed with brine, dried and concentrated. The residue was
purified by preparative HPLC to give an oil. The oil was treated with
1 equiv of 4 N HCl–EtOAc (0.085 mL) to provide 14 (0.15 g, 67%) as
white amorphous. 1H NMR (CDCl3) d: 1.12 (3H, t, J = 7.2 Hz), 1.71–
2.04 (2H, m), 2.55 (2H, q, J = 7.2 Hz), 2.69-3.18 (5H, m), 3.41-3.51
(6H, m), 3.68-3.72 (1H, m), 6.64 (1H, d, J = 9.0 Hz), 6.90 (1H, s like),
6.99-7.04 (1H, m), 7.11-7.31 (5H, m). The NMR spectrum was mea-
sured as a free base, and the amino NH signal was not observed;
ESI-MS m/z 409 [(MꢁHCl+H)+]; chemical purity: 97.9%.
To a cooled solution of 12 (0.60 g, 1.3 mmol) and Et3N (0.37 mL,
2.6 mmol) in CH3CN (10 mL) was added ethyl isocyanate (0.11 mL,
1.3 mmol) at 0 °C. After stirring at 0 °C for 30 min, the reaction
mixture was poured into H2O and extracted with EtOAc. The ex-
tract was washed with aqueous NH4Cl and brine, dried and con-
centrated. The residue was purified by preparative HPLC to
provide 18 (0.47 g, 78%) as white powder. Mp 68–70 °C; 1H NMR
(CDCl3) d: 1.12 (3H, t, J = 6.6 Hz), 1.60–1.80 (1H, m), 1.85–1.95
(1H, m), 2.95–3.06 (2H, m), 3.22–3.34 (2H, m), 3.37–3.35 (5H,
m), 3.60–3.84 (5H, m), 4.38–4.42 (1H, m), 6.65 (1H, d, J = 9.0 Hz),
6.91 (1H, d, J = 2.4 Hz), 7.02 (1H, dd, J = 8.7, 3.0 Hz), 7.12–7.17
(2H, m), 7.20–7.34 (3H, m). The cis stereochemistry was assigned
on the basis of an NOE compared with that of 19; ESI-MS m/z
452 [(M+H)+]; Anal. Calcd for C23H28N3O3F3: C, 61.19; H, 6.25; N,
9.31. Found: C, 61.02; H, 6.24; N, 9.03.
5.1.12. cis-N-[2-Methoxy-5-(trifluoromethoxy)benzyl]-1-
(methyl sulfonyl)-3-phenyl-4-piperidin-4-amine
hydrochloride (15)
To a cooled mixture of 12 (0.23 g, 0.50 mmol) and Et3N (0.14 mL,
1.00 mmol) in THF (1 mL) and DMF (0.2 mL) was added methane-
sulfonyl chloride (0.060 g, 0.52 mmol) at 0 °C. After stirring at room
temperature for 3 h, the reaction mixture was added to aqueous
NaHCO3 and extracted with EtOAc. The extract was washed with
brine, dried and concentrated. The residue was purified by prepara-
tive HPLC to give an oil, which was treated with 1 equiv of 4 N HCl–
EtOAc (0.10 mL) to give 15 (0.19 g, 83%) as white powder. Mp 175–
179 °C; 1H NMR (CDCl3) d: 1.80–1.93 (1H, m), 2.00–2.10 (1H, m),
2.85 (3H, s), 2.95–3.00 (1H, m), 3.14–3.28 (3H, m), 3.40–3.60 (3H,
m), 3.45 (3H, s), 3.65-3.76 (2H, m), 6.64 (1H, d, J = 9.0 Hz), 6.89
(1H, s like), 6.99–7.15 (3H, m), 7.20–7.35 (3H, m); Anal. Calcd for
5.1.16. trans-N-Ethyl-4-{[2-methoxy-5-(trifluoromethoxy)
benzyl]amino}-3-phenylpiperidine-1-carboxamide (19)
Compound 19 was synthesized by the similar procedure de-
scribed for 18 by using 13 and ethyl isocyanate in 42% yield as
white powder. Mp 94–96 °C; 1H NMR (CDCl3) d: 1.12 (3H, t,
J = 7.2 Hz), 1.35–1.53 (1H, m), 2.10–2.18 (1H, m), 2.55–2.88 (4H,
m), 3.21–3.31 (2H, m), 3.47 (3H, s), 3.56 (1H, d, J = 13.8 Hz), 3.74
(1H, d, J = 13.8 Hz), 3.84–3.93 (1H, m), 4.05–4.14 (1H, m), 4.37–
4.44 (1H, t like), 3.80–4.80 (1H, br), 6.68 (1H, d, J = 9.0 Hz), 6.92
(1H, d, J = 2.4 Hz), 7.03–7.12 (3H, m), 7.20–7.34 (3H, m). The trans
stereochemistry was assigned on the basis of an NOE between the
protons at C5 and benzyl carbon; ESI-MS m/z 452 [(M+H)+]; Anal.
Calcd for C23H28N3O3F3ꢀ0.1H2O: C, 60.94; H, 6.27; N, 9.27. Found:
C, 60.88; H, 6.23; N, 9.34.
C21H26ClN2O4F3Sꢀ0.5H2O: C, 50.05; H, 5.40; N, 5.56. Found: C,
49.71; H, 5.40; N, 5.46; ESI-MS m/z 459 [(M–HCl+H)+].
5.1.13. Methyl cis-4-{[2-methoxy-5-(trifluoromethoxy)benzyl]
amino}-3-phenylpiperidine-1-carboxylate hydrochloride (16)
To a cooled mixture of 12 (0.23 g, 0.50 mmol) and Et3N
(0.14 mL, 1.00 mmol) in THF (1 mL) and DMF (0.2 mL) was added
methyl chloroformate (0.050 g, 0.53 mmol) at 0 °C. After stirring
at room temperature for 3 h, the reaction mixture was added aque-
ous NaHCO3 and extracted with EtOAc. The extract was washed
with brine, dried and concentrated. The residue was purified by
preparative HPLC to give an oil, which was treated with 1 equiv
of 4 N HCl–EtOAc (0.10 mL) to provide 16 (0.19 g, 87%) as white
powder. Mp 166–170 °C; 1H NMR (CDCl3) d: 1.80–1.93 (1H, m),
2.00–2.10 (1H, m), 2.91-3.00 (3H, m), 3.10–4.15 (12H, m), 6.64
(1H, d, J = 9.0 Hz), 6.89 (1H, s like), 6.99–7.15 (3H, m), 7.20–7.35
(3H, m). The NMR spectrum was measured as a free base; Anal.
Calcd for C22H25N2O4F3ꢀHClꢀ0.5H2O: C, 54.61; H, 5.62; N, 5.79.
Found: C, 54.39; H, 5.78; N, 5.65; ESI-MS m/z 439 [(M–HCl+H)+].
5.1.17. 5-Nitro-2,3-dihydro-1-benzofuran (21)10
To a solution of 20 (27.1 g, 226 mmol) in acetic acid (100 mL)
was slowly added nitric acid (11.2 mL, 249 mmol) at 0 °C. After
stirring at room temperature for 2 h, the reaction mixture was
poured into a mixture of ice and 12 N NaOH (100 mL). The mixture
was extracted with EtOAc. The extract was washed with aqueous
NH4Cl and brine, dried and concentrated. The residue was purified
by flash chromatography on SiO2 with an eluent of 20% EtOAc/hex-
ane to provide 21 (6.4 g, 17%) as a pale brown powder; 1H NMR
(CDCl3) d: 3.30 (2H, t, J = 8.7 Hz), 4.74 (2H, t, J = 8.7 Hz), 6.81 (1H,
d, J = 9.6 Hz), 8.07–8.12 (2H, m); Anal. Calcd for C8H7NO: C,
58.18; H, 4.27; N, 8.48. Found: C, 57.93; H, 4.19; N, 8.27.
5.1.18. 2,3-Dihydro-1-benzofuran-5-ylamine (22)10
A mixture of 21 (6.3 g, 38.1 mmol) and 10% palladium on carbon
(1.0 g) in EtOH (50 mL) and THF (50 mL) was stirred under an
atmosphere of H2 (1 atm) at room temperature for 13 h. The cata-
lyst was removed by filtration, and then the filtrate was concen-
trated. The residue was purified by flash chromatography on SiO2
with a gradient eluent of 0–10% MeOH/EtOAc to provide 22
(4.63 g, 90%) as a pale brown powder; 1H NMR (CDCl3) d: 3.12
(2H, t, J = 8.6 Hz), 3.37 (2H, s), 4.49 (2H, t, J = 8.6 Hz), 6.43–6.47
5.1.14. cis-1-Acetyl-N-(2-methoxy-5-(trifluoromethoxy)benzyl)-
3-phenyl-4-piperidinamine hydrochloride (17)
To a cooled mixture of 12 (0.20 g, 0.44 mmol) and Et3N
(0.19 mL) in THF (10 mL) was added acetyl chloride (0.032 mL,
0.44 mmol) at 0 °C. After stirring at room temperature for 3 h,