228
Vol. 60, No. 2
saturated aqueous sodium bicarbonate solution, and brine, phenylacetaldehyde, in 71% yield.
dried over Na2SO4, and evaporated in vacuo to give tert-butyl
4-(2-{[(1R)-1-(4-fluorophenyl)-2-methylpropyl]amino}-2-oxo- J=6.8Hz), 1.36 1.53 (2H, m), 1.62 1.82 (2H, m), 1.83 1.96
1H-NMR (DMSO-d6) δ: 0.70 (3H, d, J=6.8Hz), 0.89 (3H, d,
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ethyl)piperidine-1-carboxylate (11.8g) as a colorless foam. To (2H, m), 2.06 2.18 (2H, m), 2.77 2.98 (4H, m), 3.10 3.20
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an ice-cooled solution of the N-Boc derivative obtained above (2H, m), 3.36 3.48 (2H, m), 3.74 (3H, s), 4.54 (1H, dd, J=8.8,
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(11.8g) in AcOEt (50mL) was added 4M HCl–AcOEt (50mL, 9.2Hz), 6.78 6.85 (3H, m), 7.13 (2H, dd, J=7.6, 8.0Hz),
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200mmol) and the mixture was stirred at room temperature 7.20 7.32 (3H, m), 8.31 (1H, d, J=9.2Hz). MS (FAB) m/z:
for 16h. The reaction mixture was concentrated in vacuo and 427 (M++1). Anal. Calcd for C26H35N2O2F·C2H2O4: C, 65.10;
partitioned between CHCl3 and aqueous potassium carbonate H, 7.22; N, 5.42; F, 3.68. Found: C, 64.99; H, 7.22; N, 5.39; F,
solution. The organic layer was washed with brine, dried over 3.70.
Na2SO4, and evaporated in vacuo to give the title compound 6
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-2-{1-[2-(4-
(8.54g, 2 steps 98%) as a colorless solid.
methoxyphenyl)ethyl]piperidin-4-yl}acetamide Oxalate (4d)
1H-NMR (CDCl3) δ: 0.82 (3H, d, J=6.8Hz), 0.96 (3H, d, The title compound was prepared in the same manner as de-
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J=6.8Hz), 1.05 1.19 (2H, m), 1.54 1.74 (2H, m), 1.85
scribed for 4a using 4-methoxyphenylacetaldehyde instead of
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2.05 (2H, m), 2.09 (2H, d, J=7.2Hz), 2.56 2.65 (2H, m), phenylacetaldehyde, in 74% yield.
2.97 3.07 (2H, m), 4.72 (1H, dd, J=8.4, 8.4Hz), 5.69 (1H, d,
1H-NMR (DMSO-d6) δ: 0.70 (3H, d, J=6.8Hz), 0.88 (3H, d,
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J=8.4Hz), 7.00 (2H, dd, J=8.4, 8.8Hz), 7.19 (2H, dd, J=5.2, J=6.8Hz), 1.36 1.51 (2H, m), 1.62 1.82 (2H, m), 1.83 1.96
8.8Hz). MS (FAB) m/z: 293 (M++1).
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(2H, m), 2.06 2.18 (2H, m), 2.77 2.94 (4H, m), 3.05 3.15
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N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-2-[1-(2- (2H, m), 3.35 3.48 (2H, m), 3.72 (3H, s), 4.54 (1H, dd, J=8.4,
phenylethyl)piperidin-4-yl]acetamide Oxalate (4a) (Method 8.8Hz), 6.89 (2H, d, J=8.8Hz), 7.09 7.19 (4H, m), 7.29 (2H,
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A) To an ice-cooled mixture of 6 (0.45g, 1.54mmol), phen- dd, J=5.6, 8.4Hz), 8.30 (1H, d, J=8.8Hz). MS (FAB) m/z:
ylacetaldehyde (0.26g, 2.16mmol), and acetic acid (0.3mL) 427 (M++1). Anal. Calcd for C26H35N2O2F·C2H2O4: C, 65.10;
in CH2Cl2 (10mL) was added sodium triacetoxyborohydride H, 7.22; N, 5.42; F, 3.68. Found: C, 65.11; H, 7.30; N, 5.38; F,
(0.60g, 2.83mmol) and the mixture was stirred at room 3.70.
temperature for 25h. The reaction mixture was concen-
2-{1-[2-(3,4-Dimethoxyphenyl)ethyl]piperidin-4-yl}-N-
trated in vacuo and partitioned between saturated aqueous [(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Oxalate
sodium bicarbonate solution and CHCl3. The organic layer (4e) The title compound was prepared in the same manner
was dried over Na2SO4 and evaporated in vacuo. The result- as described for 4a using 3,4-dimethoxyphenylacetaldehyde
ing residue was purified by column chromatography on silica instead of phenylacetaldehyde, in 48% yield.
gel (MeOH/CHCl3=3/97) to give N-[(1R)-1-(4-fluorophenyl)-
2-methylpropyl]-2-[1-(2-phenylethyl)piperidin-4-yl]acetamide (3H, d, J=6.8Hz), 1.36 1.52 (2H, m), 1.62 1.82 (2H, m),
1H-NMR (DMSO-d6) δ: 0.70 (3H, d, J=6.8Hz), 0.89
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(0.60g) as a colorless solid. The compound was converted to 1.82 1.96 (2H, m), 2.06 2.18 (2H, m), 2.77 2.93 (4H, m),
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its oxalate by treating it with oxalic acid (0.14g, 1.55mmol). 3.08 3.18 (2H, m), 3.35 3.49 (2H, m), 3.72 (3H, s), 3.74 (3H,
The crude salt was suspended with CH3CN and filtered to s), 4.54 (1H, dd, J=8.8, 9.2Hz), 6.75 (1H, dd, J=1.6, 8.0Hz),
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give the title compound 4a (0.37g, 49%) as a colorless powder. 6.84 6.91 (2H, m), 7.13 (2H, dd, J=8.4, 8.8Hz), 7.29 (2H,
1H-NMR (DMSO-d6) δ: 0.70 (3H, d, J=6.4Hz), 0.89 (3H, d, dd, J=5.6, 8.4Hz), 8.31 (1H, d, J=9.2Hz). MS (FAB) m/z: 457
J=6.4Hz), 1.35 1.53 (2H, m), 1.62 1.82 (2H, m), 1.83 1.97 (M++1). Anal. Calcd for C27H37N2O3F·C2H2O4: C, 63.72; H,
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(2H, m), 2.06 2.18 (2H, m), 2.76 2.91 (2H, m), 2.91 3.00 7.19; N, 5.12; F, 3.48. Found: C, 63.62; H, 7.23; N, 5.11; F, 3.51.
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(2H, m), 3.09 3.20 (2H, m), 3.36 3.50 (2H, m), 4.54 (1H,
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-
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dd, J=8.8, 8.8Hz), 7.13 (2H, dd, J=7.6, 8.0Hz), 7.22 7.36 (2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide
(7H, m), 8.30 (1H, d, J=8.8Hz). MS (FAB) m/z: 397 (M++1). Hydrochloride (4f) (Method B) To a mixture of 6 (7.80g,
Anal. Calcd for C25H33N2OF·C2H2O4: C, 66.65; H, 7.25; N, 26.7mmol) and K2CO3 (6.0g, 43.4mmol) in CH3CN (100mL)
5.76; F, 3.90. Found: C, 66.60; H, 7.24; N, 5.74; F, 3.94.
was added 14 (10.7g, 30.5mmol) and the mixture was stirred
°
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-2-{1-[2-(2- at 50 C for 20h. The reaction mixture was concentrated in
methoxyphenyl)ethyl]piperidin-4-yl}acetamide Oxalate (4b) vacuo and the resulting residue was partitioned between
The title compound was prepared in the same manner as de- H2O and AcOEt. The organic layer was washed with brine,
scribed for 4a using 2-methoxyphenylacetaldehyde instead of dried over Na2SO4 and evaporated in vacuo. The resulting
phenylacetaldehyde, in 72% yield.
residue was purified by column chromatography on silica
1H-NMR (DMSO-d6) δ: 0.70 (3H, d, J=6.8Hz), 0.89 gel (MeOH/CHCl3=5/95) to give N-[(1R)-1-(4-fluorophenyl)-
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(3H, d, J=6.8Hz), 1.35 1.53 (2H, m), 1.62 1.82 (2H, m), 2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}-
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1.83 1.98 (2H, m), 2.06 2.19 (2H, m), 2.80 2.98 (4H, m), piperidin-4-yl)acetamide (12.4g) as a colorless solid. The
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3.03 3.12 (2H, m), 3.37 3.50 (2H, m), 3.79 (3H, s), 4.54 (1H, compound was converted to its hydrochloride salt by treating
dd, J=8.8, 8.8Hz), 6.90 (1H, dd, J=7.6, 8.0Hz), 6.99 (1H, d, it with 4M HCl–AcOEt (7.0mL, 28.0mmol). The crude salt
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J=8.0Hz), 7.09 7.20 (3H, m), 7.22 7.33 (3H, m), 8.32 (1H, was suspended with CH3CN and filtered to give the title com-
d, J=8.8Hz). MS (FAB) m/z: 427 (M++1). Anal. Calcd for C2 pound 4f (10.93g, 81%) as a colorless powder.
1
6H35N2O2F·C2H2O4: C, 65.10; H, 7.22; N, 5.42; F, 3.68. Found:
C, 64.99; H, 7.29; N, 5.43; F, 3.68.
[α]D25 +46.50 (c=1.00, MeOH). H-NMR (DMSO-d6) δ: 0.70
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(3H, d, J=6.8Hz), 0.89 (3H, d, J=6.8Hz), 1.48 1.82 (4H, m),
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N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-2-{1-[2-(3- 1.84 1.98 (2H, m), 2.07 2.18 (2H, m), 2.82 3.04 (4H, m),
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methoxyphenyl)ethyl]piperidin-4-yl}acetamide Oxalate (4c) 3.06 3.16 (2H, m), 3.31 (3H, s), 3.42 3.53 (2H, m), 3.67
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The title compound was prepared in the same manner as de- 3.73 (2H, m), 4.08 4.15 (2H, m), 4.54 (1H, dd, J=8.4, 8.8Hz),
scribed for 4a using 3-methoxyphenylacetaldehyde instead of 6.91 (1H, dd, J=7.2, 7.6Hz), 7.00 (1H, d, J=7.6Hz), 7.13 (2H,