L. Lipani et al. / European Journal of Medicinal Chemistry 86 (2014) 578e588
585
prop CH2-3), 4.88 (s, 2H, CH2-Ph), 5.90 (d, J ¼ 7.9 Hz, 1H, CH-5), 6.96
(d, J ¼ 8.7 Hz, 2H, HA), 7.33 (m, 2H, HA) 7.58e7.97 (m, 5H, HA-N3),
4.1.4.6. tert-Butyl-5-methyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)pro-
poxy]phenyl}methyl)-1,2,3,4-tetrahydro pyrimidine-1-carboxylate
(13). Compound 13 was prepared from 6 and P3 according to the
general procedure described above to obtain product 9e12. Yield
31.43% (colorless solid). Rf ¼ 0.52 (DCM:MeOH, 9:1, ammonia at-
8.05 (d, J ¼ 7.9 Hz, 1H, CH-6); 13C NMR (100 MHz, DMSO):
d [ppm]
23.86 (pip CH2-4), 25.33 (pip CH2-3,5), 26.06 (prop CH2-2), 49.37
(CH2-Ph), 53.59 (pip CH2-2,6), 54.87 (prop CH2-1), 66.07 (prop CH2-
3), 100.94 (CH-5), 114.89 (CA0-2,6), 128.07 (CA00-3,5), 128.11 (CA0-
3,5), 129.03 (CA00-2,6), 130.31 (CA00-4), 132.51 (CA00-1), 135.45 (CA0-
4), 149.77 (CH-6), 151.23 (C-2), 158.39 (C-4), 162.25 (CA0-1), 167.57
(CO). ESI-MS (Mþ2Hþ) 449.1; HRMS (MþHþ) calculated
mosphere); 1H NMR (400 MHz, DMSO):
d [ppm] 1.38 (m, 6H, pip
CH2e3,4,5), 1.51 (s, 9H, tBuO), 1.76 (m, 2H, prop CH2e2), 2.40 (s, 3H,
CH3-5), 2.49 (m, 6H, pip CH2-2,6, prop CH2-1), 3.94 (t, J ¼ 6.8 Hz, 2H,
prop CH2-3), 4.86 (s, 2H, CH2-Ph), 6.83 (d, J ¼ 8.6 Hz, 2H, HA), 7.19
(d, J ¼ 8.6 Hz, 2H, HA), 7.32 (s, 1H, CH-6); 13C NMR (100 MHz,
C
26H30N3O4: 448.22308, found: 448.22276.
DMSO):
d [ppm] 12.40 (CH3-5), 23.54 (pip CH2-4, prop CH2-2),
24.94 (pip CH2-3,5), 25.67 (tBu-CH3), 42.21 (CH2-Ph), 53.67 (pip
CH2-2,6), 54.76 (prop CH2-1), 62.51 (prop CH2-3), 65.68 (tBu-C),
107.23 (C-5), 114.17 (CA-2,6), 129.39 (CA-3,5), 134.49 (CA-4), 136.42
(CH-6), 148.44 (C-2), 151.28 (CO), 157.69 (CA-1), 163.71 (C-4). ESI-
MS (MþHþ) 458.4.
4.1.4.3. 3-Benzoyl-5-methyl-1-({4-[3-(piperidin-1-yl)propoxy]
phenyl}methyl)-1,2,3,4-tetrahydro pyrimidine-2,4-dione (10).
Compound 10 was prepared from 3 and P3 according to the pro-
cedure described above to obtain 9. Yield 39.91% (yellow oil).
Rf ¼ 0.80 (DCM:MeOH, 9:1, ammonia atmosphere); 1H NMR
(250 MHz, DMSO): d [ppm] 1.46 (m, 6H, pip CH2e3,4,5),1.90 (m, 5H,
4.1.4.7. tert-Butyl-5,6-dimethyl-2,4-dioxo-3-({4-[3-(piperidin-1-yl)
propoxy]phenyl}methyl)-1,2,3,4-tetrahydropyrimidine-1-carboxylate
(14). Compound 14 was prepared from 7 and P3 according to the
general procedure described above to obtain compound 9e13.
Yield 37.65% (colorless oil). Rf ¼ 0.67 (DCM:MeOH, 9:1, ammonia
prop CH2-2, CH3-5 ), 2.41 (m, 6H, pip CH2-2,6, prop CH2-1), 4.05 (t,
J ¼ 6.3 Hz, 2H, prop CH2-3), 4.90 (s, 2H, CH2-Ph), 7.00e6.98 (d,
J ¼ 8.7 Hz, 2H, HA), 7.33 (d, J ¼ 8.7 Hz, 2H, HA), 7.64 (m, 5H, HA),
8.01 (m, 1H, CH-6); 13C NMR (62 MHz, DMSO):
d [ppm] 11.84 (CH3-
atmosphere); 1H NMR (400 MHz, DMSO):
d [ppm] 1.39 (m, 2H, pip
5), 23.96 (pip CH2-4), 25.41 (pip CH2-3,5), 26.09 (prop CH2-2), 50.26
(CH2-Ph), 53.96 (pip CH2-2,6), 54.99 (prop CH2-1), 65.90 (prop CH2-
3), 109.00 (C-5), 114.60 (CA0-2,6), 129.30 (CA00-3,5), 129.47 (CA0-3,5),
130.20 (CA00-2,6), 131.16 (CA00-4), 132.40 (CA00-1), 135.40 (CA0-4),
150.95 (CH-6), 158.30 (C-2), 162.79 (C-4), 167.55 (CA0-1), 169.68
(CO); ESI-MS (Mþ2Hþ) 463.0; HRMS (MþHþ) calculated
CH2e4), 1.50 (m, 4H, pip CH2e3,5), 1.54 (s, 9H, tBuO), 1.86 (m, 5H,
CH3-6, prop CH2e2), 2.20 (s, 3H, CH3-5), 2.35 (m, 6H, pip CH2-2,6,
prop CH2-1), 3.99 (t, J ¼ 6.3 Hz, 2H, prop CH2-3), 5.07 (s, 2H, CH2-
Ph), 6.94(d, J ¼ 8.6 Hz, 2H, HA), 7.15 (d, J ¼ 8.6 Hz, 2H, HA) 13C NMR
(62 MHz, DMSO):
d [ppm] 9.14 (CH3-5), 10.74 (CH3-6), 16.33 (pip
C
27H32N3O4: 462.23873, found: 462.23846.
CH2-4), 24.02 (prop CH2-2), 25.47 (pip CH2-3,5), 27.10 (tBu-CH3),
46.66 (CH2-Ph), 54.01 (pip CH2-2,6), 55.04 (prop CH2-1), 65.90
(prop CH2-3), 85.80 (tBu-C), 106.38 (C-5), 114.78 (CA-2,6), 127.58
(CA-3,5), 128.28 (CA-4), 148.05 (C-2), 148.98 (C-6), 150.27 (CA-1),
157.97 (C-4), 160.00 (CO). ESI-MS (MþHþ) 472.9; HRMS (MþHþ)
calculated C26H38N3O5: 472.28060, found: 472.28123.
4.1.4.4. 3-Benzoyl-5,6-dimethyl-1-({4-[3-(piperidin-1-yl)propoxy]
phenyl}methyl)-1,2,3,4-tetra-hydropyrimidine-2,4-dione (11).
Compound 11 was prepared from 4 and P3 according to the general
procedure described above to synthesize 9 and 10. Yield 25.68%
(yellow oil). Rf ¼ 0.77 (DCM:MeOH, 9:1, ammonia atmosphere); 1H
4.1.4.8. 1-[3-(Piperidin-1-yl)propyl]-1,2,3,4-tetrahydropyrimidine-
NMR (400 MHz, DMSO):
d [ppm] 1.49 (m, 6H, pip CH2e3,4,5), 1.91
2,4-dione (15). Compound 15 was synthesized from
8
(m, 2H, prop CH2-2), 1.94 (s, 3H, CH3-6), 2.31 (s, 3H, CH3-5), 2.40 (m,
6H, pip CH2-2,6, prop CH2-1), 4.04 (t, J ¼ 6.3 Hz, 2H, prop CH2-3),
5.13 (s, 2H, CH2-Ph), 6.99(d, J ¼ 8.7 Hz, 2H, HA), 7.21 (d, J ¼ 8.7 Hz,
(0.175 mmol). The reaction was carried out in NH3/MeOH (30 mL),
and after stirring at 60 ꢁC for 4 h, products were concentrated under
reduced pressure, the residue was extracted with ethylacetate,
dried with MgSO4, and solvent removed under reduced pressure.
After purification using column chromatography (DCM:MeOH,
9:1), the final product was recrystallized from diethyl ether. Yield
71.94% (colorless solid). Mp 158 ꢁC; Rf ¼ 0.27 (DCM:MeOH, 9:1); 1H
2H, HA), 7.68(m, 5H, HA-N3); 13C NMR (100 MHz, DMSO):
d [ppm]
10.74 (CH3-5), 16.42 (CH3-6), 24.05 (pip CH2-4), 25.50 (prop CH2-2),
26.20 (pip CH2-3,5), 46.48 (CH2-Ph), 54.04 (pip CH2-2,6), 55.06
(prop CH2-1), 65.91 (prop CH2-3), 106.81 (C-5), 114.80 (CA0-2,6),
127.56 (CA00-3,5), 128.35 (CA0-3,5), 129.51 (CA00-2,6), 130.19 (CA00-4),
131.18 (CA00-1), 135.37 (CA0-4), 149.98 (C-6), 150.68 (C-2), 157.96
(CA0-1), 161.72 (C-4), 169.50 (CO); ESI-MS (Mþ2Hþ) 477.2; HRMS
(MþHþ) calculated C28H34N3O4: 476.25438, found: 476.25359.
NMR (250 MHz, DMSO):
d [ppm] 1.43 (m, 6H, pip CH2-3,4,5), 1.75
(m, 2H, prop CH2-2), 2.31 (m, 6H, pip CH2-2,6, prop CH2-1), 3.69 (t,
J ¼ 6.8 Hz, 2H, CH2-3), 5.53 (d, J ¼ 7.8 Hz, 1H, CH-5), 7.63 (d,
J ¼ 7.8 Hz,1H, CH-6) 11.19 (brs,1H, NH); 13C NMR (100 MHz, DMSO):
d
[ppm] 24.00 (pip CH2-4), 25.05 (prop CH2-2), 25.40 (pip CH2-3,5),
4.1.4.5. tert-Butyl-2,4-dioxo-3-(4-(3-(piperidin-1-yl)
benzyl)-3,4-dihydropyrimidine-1(2H)-carboxylate
propoxy)
46.22 (prop CH2-1), 53.76 (pip CH2-2,6), 55.13 (prop CH2-3) 100.43
(CH-5), 145.96 (CH-6), 150.95 (C-2), 163.79 (C-4) ppm. ESI-MS
(MþHþ) 238.7; HRMS (MþHþ) calculated C12H20N3O2: 238.15500,
found: 238.15552.
(12).
Compound 12 was prepared from 5 and P3 according to the general
procedure described above for obtaining the products 9e11. Yield
9.97% (light yellow solid). Mp 141 ꢁC; Rf ¼ 0.48 (DCM:MeOH, 9:1,
ammonia atmosphere); 1H NMR (250 MHz, DMSO):
d
[ppm] 1.47
4.1.4.9. 1-(4-(3-(Piperidin-1-yl)propoxy)benzyl)pyrimidine-
2,4(1H,3H)-dione (16). Compound 16 was synthesized by refluxing
9 (0.498 mmol) in NH3/MeOH (30 mL) for 4 h. Upon reaction
completion, solvents were evaporated under reduced pressure; the
residue was extracted with ethylacetate. The organic layer was
separated, dried over MgSO4 and evaporated under reduced pres-
sure; after purification by column chromatography (DCM:MeOH,
9:1, ammonia atmosphere), the crude product was recrystallized
from diethylether. Yield 91.16% (yellowish solid). Mp 189 ꢁC;
Rf ¼ 0.58 (DCM:MeOH, 9:1, ammonia atmosphere); 1H NMR
(m, 6H, pip CH2e3,4,5), 1.59 (s, 9H, tBuO), 1.91 (m, 2H, prop CH2-2),
2.42 (m, 6H, pip CH2-2,6, prop CH2-1), 4.02 (t, J ¼ 6.3 Hz, 2H, prop
CH2-3), 4.92 (s, 2H, CH2-Ph), 5.93 (d, J ¼ 8.3 Hz, 1H, CH-5), 6.92(d,
J ¼ 8.6 Hz, 2H, HA), 7.18 (d, J ¼ 8.6 Hz, 2H, HA), 8.03 (d, J ¼ 8.3 Hz,1H,
CH-6); 13C NMR (100 MHz, DMSO):
d [ppm] 24.03 (pip CH2-4),
25.48 (pip CH2-3,5, prop CH2-2), 26.19 (tBu-CH3), 41.93 (CH2-Ph),
54.03 (pip CH2-2,6), 55.06 (prop CH2-1), 65.84 (prop CH2-3), 99.78
(CH-5), 114.17 (CA-2,6), 129.27 (CA-3,5), 140.76 (CA-4), 151.42 (CH-
6), 157.79 (C-2), 163.01 (C-4). ESI-MS (Mþ2Hþ) 445.2; HRMS
(MþHþ) calculated C24H34N3O5: 444.24930, found: 444.24897.
(250 MHz, DMSO): d [ppm] 1.43 (m, 6H, pip CH2-3,4,5), 1.89 (m, 2H,