9810
N. Fujiwara et al. / Bioorg. Med. Chem. 16 (2008) 9804–9816
(3H, s), 3.04–2.84 (2H, br m), 2.69–2.62 (1H, m), 1.87–1.66 (4H, m);
MS (ESI, positive) m/z 463 (M+1); Anal. Calcd for C26H30N4O4: C,
67.51; H, 6.54; N, 12.11. Found: C, 67.49; H, 6.49; N, 12.12.
m), 1.86–1.76 (2H, m), 1.61–1.40 (2H, m); MS (ESI, positive) m/z
461 (M+1); Anal. Calcd for C26H28N4O4: C, 67.81; H, 6.13; N,
12.17. Found: C, 67.62; H, 6.12; N, 12.18.
4.1.9. 4-{1-[(3,4-Dichlorophenyl)carbonyl]piperidin-4-yl}-6-(4-
methoxybenzyl)pyrimidin-2-amine (7)
4.1.14. 4-[1-(1,3-Benzodioxol-4-ylcarbonyl)piperidin-4-yl]-6-
(4-methoxybenzyl)pyrimidin-2-amine (12)
A white solid from MeOH (272 mg, 86%), mp 195–196 °C; 1H
NMR (CDCl3) d 7.52–7.48 (2H, m), 7.26–7.24 (1H, m), 7.16 (2H, d,
J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.26 (1H, s), 4.95 (2H, s), 4.80–
4.71 (1H, br m), 3.83 (2H, s), 3.80 (3H, s), 3.82–3.73 (1H, br m),
3.13–3.03 (1H, br m), 2.87–2.78 (1H, br m), 2.70–2.62 (1H, m),
1.94–1.69 (4H, br m); MS (ESI, positive) m/z 471 (M+1); Anal. Calcd
for C24H24Cl2N4O2: C, 61.15; H, 5.13; Cl, 15.04; N, 11.89. Found: C,
61.06; H, 5.10; Cl, 14.96; N, 11.94.
A white solid from iPrOH (488 mg, 82%), mp 167–167.5 °C; 1H
NMR (CDCl3) d 7.16 (2H, t, J = 5.9 Hz), 6.91–6.85 (5H, m), 6.26
(1H, s), 5.99 (2H, s), 4.95 (2H, s), 4.83–4.81 (1H, m), 3.83 (2H, s),
3.81–3.76 (1H, m), 3.12 (1H, t, J = 12.4 Hz), 2.82 (1H, t,
J = 12.1 Hz), 2.68–2.61 (1H, m), 1.95–1.68 (4H, m); MS (ESI, posi-
tive) m/z 447 (M+1); Anal. Calcd for C25H26N4O4: C, 67.25; H,
5.87; N, 12.55. Found: C, 67.10; H, 5.88; N, 12.58.
4.1.15. 4-[1-(2,3-Dihydro-1,4-benzodioxin-6-ylcarbonyl)-
piperidin-4-yl]-6-(4-methoxybenzyl)pyrimidin-2-amine (13)
A white solid from iPrOH (568 mg, 92%), mp 187–188 °C; 1H
NMR (CDCl3) d 7.16 (2H, d, J = 8.5 Hz), 6.96 (1H, d, J = 2.0 Hz),
6.92 (1H, dd, J = 8.0, 2.0 Hz), 6.87–6.85 (3H, m), 6.26 (1H, s), 4.93
(2H, s), 4.80–4.67 (1H, br m), 4.27 (4H, s), 4.08–3.91 (1H, br m),
3.83 (2H, s), 3.80 (3H, s), 3.03–2.85 (2H, br m), 2.68–2.60 (1H,
m), 1.86–1.67 (4H, m); MS (ESI, positive) m/z 461 (M+1); Anal.
Calcd for C26H28N4O4: C, 67.81; H, 6.13; N, 12.17. Found: C,
67.59; H, 6.14; N, 12.04.
4.1.10. 4-(1-Acetylpiperidin-4-yl)-6-(4-methoxybenzyl)pyri-
midin-2-amine (10)
A white solid from EtOH (227 mg, 99%), mp 203–205 °C, 1H
NMR (CDCl3) d 7.16 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz),
6.24 (1H, s), 4.96 (2H, s), 4.73–4.68 (1H, m), 3.91–3.86 (1H, m),
3.82 (2H, s), 3.80 (3H, s), 3.10 (1H, td, J = 13.0, 2.7 Hz), 2.64–2.55
(2H, m), 2.10 (3H, s), 1.89–1.81 (2H, m), 1.69–1.54 (2H, m); MS
(ESI, positive) m/z 341 (M+1); Anal. Calcd for C19H24N4O2.0.25H2O:
C, 66.16; H, 7.16; N, 16.24. Found: C, 65.92; H, 7.06; N, 16.07.
4.1.11. 4-(4-Methoxybenzyl)-6-(1-octanoylpiperidin-4-
yl)pyrimidin-2-amine (11)
4.1.16. 4-[1-(2,3-Dihydro-1-benzofuran-5-ylcarbonyl)piper-
idin-4-yl]-6-(4-methoxybenzyl)pyrimidin-2-amine (14)
A white solid from iPrOH (581 mg, 98%), mp 162–264 °C; 1H
NMR (CDCl3) d 7.31 (1H, s), 7.20–7.15 (3H, m), 6.86 (2H, d,
J = 8.5 Hz), 6.77 (1H, d, J = 8.0 Hz), 6.27 (1H, s), 4.94 (2H, s), 4.83–
4.67 (1H, br m), 4.61 (2H, t, J = 8.7 Hz), 4.29–3.93 (1H, br m), 3.83
(2H, s), 3.80 (3H, s), 3.23 (2H, t, J = 8.7 Hz), 3.02–2.86 (2H, br m),
2.68–2.61 (1H, m), 1.87–1.67 (4H, m); MS (ESI, positive) m/z 445
(M+1); Anal. Calcd for C26H28N4O3: C, 70.25; H, 6.35; N, 12.60.
Found: C, 70.47; H, 6.38; N, 12.63.
A white solid from hexane/EtOH (230 mg, 90%), mp 101–103 °C;
1H NMR (CDCl3) d 7.16 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz),
6.24 (1H, s), 4.93 (2H, s), 4.75–4.70 (1H, m), 3.96–3.90 (1H, m),
3.82 (2H, s), 3.80 (3H, s), 3.10–3.02 (1H, m), 2.64–2.54 (2H, m),
2.32 (2H, t, J = 7.7 Hz), 1.90–1.81 (2H, m), 1.65–1.55 (4H, m),
1.32–1.28 (8H, m), 0.88 (3H, t, J = 7.0 Hz); MS (ESI, positive) m/z
425 (M+1); Anal. Calcd for C25H36N4O2: C, 70.72; H, 8.55; N,
13.20. Found: C, 70.61; H, 8.56; N, 13.16.
4.1.12. 4-{1-[(3,4-Dimethoxyphenyl)acetyl]piperidin-4-yl}-6-
(4-methoxybenzyl)pyrimidin-2-amine (8)
4.1.17. 4-[1-(1-Benzofuran-5-ylcarbonyl)piperidin-4-yl]-6-(4-
methoxybenzyl)pyrimidin-2-amine (15)
To a solution of 51 (200 mg, 0.67 mmol), 3,4-dimethoxyphenyl-
acetic acid (138 mg, 0.70 mmol), and 1-hydroxybenzotriazole
(HOBt, 95 mg, 0.70 mmol) in CHCl3 (100 ml) was added N-ethyl-
A white solid from EtOH (459 mg, 77%), mp 188–188.5 °C; 1H
NMR (CDCl3) d 7.69–7.67 (2H, m), 7.52 (1H, d, J = 8.3 Hz), 7.37
(1H, dd, J = 8.3, 1.5 Hz), 7.17 (2H, d, J = 8.8 Hz), 6.86 (2H, d,
J = 8.8 Hz), 6.80 (1H, dd, J = 2.2, 1.0 Hz), 6.27 (1H, s), 4.96 (2H, s),
4.84–4.78 (1H, br m), 3.96–3.88 (1H, br m), 3.83 (2H, s), 3.80
(3H, s), 3.05–2.88 (2H, br m), 2.70–2.62 (1H, m), 1.88–1.72 (4H,
br m); MS (ESI, positive) m/z 443 (M+1); Anal. Calcd for
C26H26N4O3: C, 70.57; H, 5.92; N, 12.66. Found: C, 70.50; H, 5.95;
N, 12.69.
N0-[3-(dimethylamino)propyl]carbodiimide
hydrochloride
(EDCꢂHCl, 135 mg, 0.70 mmol) at room temperature under nitro-
gen atmosphere. After stirring for 2 h, the mixture was washed
successively with aqueous satd NaHCO3 and brine. The organic
layer was dried over Na2SO4, and then evaporated. The residue
was purified by silica gel column chromatography using CHCl3/
MeOH (50:1, v/v) as eluent. Crystallization from iPrOH gave 8
(308 mg, 96%) as a white solid: mp 140–140.5 °C; 1H NMR (CDCl3)
d 7.15 (2H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 6.82–6.79 (2H, m),
6.75 (1H, dd, J = 8.3, 2.0 Hz), 6.19 (1H, s), 4.94 (2H, s), 4.75–4.71
(1H, m), 3.97–3.93 (1H, m), 3.88 (3H, s), 3.86 (3H, s), 3.81 (2H, s),
3.80 (3H, s), 3.69 (2H, s), 3.05–2.98 (1H, m), 2.65–2.52 (2H, m),
1.84–1.70 (2H, m), 1.62–1.52 (1H, m), 1.44–1.33 (1H, m); MS
(ESI, positive) m/z 477 (M+1); Anal. Calcd for C27H32N4O4: C,
68.05; H, 6.77; N, 11.76. Found: C, 67.96; H, 6.78; N, 11.78.
Compounds 9 and 12–20 were prepared using a procedure sim-
ilar to that for the preparation of 8.
4.1.18. 4-[1-(1-Benzofuran-6-ylcarbonyl)piperidin-4-yl]-6-(4-
methoxybenzyl)pyrimidin-2-amine (16)
A white solid from MeOH (520 mg, 88%), mp 186–187 °C; 1H
NMR (CDCl3) d 7.70 (1H, d, J = 2.2 Hz), 7.63–7.59 (2H, m), 7.31
(1H, dd, J = 7.9, 1.1 Hz), 7.17 (2H, d, J = 8.5 Hz), 6.86 (2H, d,
J = 8.5 Hz), 6.80 (1H, dd, J = 2.2, 1.1 Hz), 6.28 (1H, s), 4.94 (2H, s),
4.85–4.76 (1H, br m), 4.00–3.91 (1H, br m), 3.84 (2H, s), 3.80
(3H, s), 3.05–2.92 (2H, br m), 2.69–2.63 (1H, m), 1.88–1.73 (4H,
br m); MS (ESI, positive) m/z 443 (M+1); Anal. Calcd for
C26H26N4O3: C, 70.57; H, 5.92; N, 12.66. Found: C, 70.36; H, 5.95;
N, 12.69.
4.1.13. 4-[1-(1,3-Benzodioxol-5-ylacetyl)piperidin-4-yl]-6-(4-
methoxybenzyl)pyrimidin-2-amine (9)
4.1.19. 4-[1-(1,3-Benzoxazol-5-ylcarbonyl)piperidin-4-yl]-6-(4-
methoxybenzyl)pyrimidin-2-amine (17)
A white solid from iPrOH, (198 mg, 86%), 155–156 °C; 1H NMR
(CDCl3) d 7.15 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 6.77–
6.74 (2H, m), 6.67 (1H, dd, J = 7.9, 1.6 Hz), 6.21 (1H, s), 5.94 (2H,
s), 4.93 (2H, s), 4.74–4.69 (1H, m), 3.97–3.91 (1H, m), 3.82 (2H,
s), 3.80 (3H, s), 3.64 (2H, s), 3.06–2.99 (1H, m), 2.66–2.53 (2H,
A white solid from MeOH (524 mg, 88%), mp 178–179 °C; 1H
NMR (CDCl3) d 8.16 (1H, s), 7.86 (1H, d, J = 1.5 Hz), 7.63 (1H, d,
J = 8.5 Hz), 7.50 (1H, dd, J = 8.5, 1.5 Hz), 7.17 (2H, d, J = 8.5 Hz),
6.86 (2H, d, J = 8.5 Hz), 6.27 (1H, s), 4.96 (2H, s), 4.90–4.77 (1H,