5522
N. Zidar et al. / European Journal of Medicinal Chemistry 46 (2011) 5512e5523
brine (2 ꢂ 15 mL), dried over Na2SO4 and concentrated under
4.6.6. General procedure H. synthesis of compounds 62 and 63
A suspension of cesium carbonate (463 mg, 1.43 mmol) and
uracil (159 mg, 1.43 mmol) in DMF (10 mL) was stirred at room
temperature for 15 min. The solution of 60 or 61 (411 mg,
0.947 mmol) in DMF (5 mL) was added and the mixture stirred at
room temperature for 3 h. Water (20 mL) was added, the mixture
acidified to pH 5 with 1 M HCl, and extracted with ethyl acetate
(2 ꢂ 20 mL). The organic phase was washed with water (2 ꢂ 15 mL),
and brine (2 ꢂ 15 mL), dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography using dichloromethane/methanol as an eluent.
reduced pressure. Yield, 58% (2.70 g); white crystals; mp 80e82 ꢀC;
23
[
a
]
þ 26.1 (c 0.416, DMF); IR (KBr)
n
¼ 3290, 3049, 3008, 2954,
D
2851,1751,1733,1640,1531,1440,1412,1383,1360,1310,1296,1262,
1234,1205,1150,1110, 987, 811, 819, 700, 659 cme1 1H NMR (DMSO-
d6)
d
1.96e2.20 (m, 2H, CHCH2CH2), 2.47 (t, 2H, 3J ¼ 7.5 Hz,
CHCH2CH2), 3.59 (s, 3H, CH3), 3.66 (s, 3H, CH3), 4.45e4.53 (m, 1H,
CHCH2CH2), 4.83 (s, 2H, CH2Cl), 7.50 (t, 1H, 3J ¼ 7.8 Hz, Ar-H-5), 7.63
(d, 1H, 3J ¼ 7.8 Hz, Ar-H-4), 7.86 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-6), 7.95 (s,
1H, Ar-H-2), 8.81 (d, 1H, 3J ¼ 7.5 Hz, NH); 13C NMR (CDCl3)
d 26.98
(CH2), 30.25 (CH2), 45.56 (CH2Cl), 51.95 (CH/CH3), 52.36 (CH/CH3),
52.64 (CH/CH3), 127.01, 127.46, 129.04, 131.91, 134.06, 138.04, 166.66
(CO), 172.41 (CO), 173.68 (CO); MS (ESI) m/z (%) ¼ 350 (MNaþ, 40),
328 (MHþ, 60), 85 (100). Anal. (C15H18ClNO5) C, H, N.
4.6.6.1. (R)-dimethyl 2-(3e((4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)methyl)phenoxy)methyl) benzamido)pentanedioate (62). Yield,
40% (193 mg); white crystals; mp 65e67 ꢀC; [
a]
23 þ 11.7 (c 0.214,
D
4.6.4.2. (R)-dimethyl
benzamido)pentanedioate (58). Synthesized according to General
procedure from 4-(hydroxymethyl)phenol (57, 114 mg,
2-(3e((4-(Hydroxymethyl)phenoxy)methyl)
DMF); IR (KBr)
n
¼ 3422, 3054, 2953, 2876, 1737, 1681, 1611, 1534,
1513, 1457, 1438, 1385, 1349, 1301, 1240, 1176, 1102, 1014, 810,
F
750 cme1 1H NMR (DMSO-d6)
d 1.96e2.19 (m, 2H, CHCH2CH2), 2.46
0.915 mmol) and 56 (300 mg, 0.915 mmol). The crude product was
purified by flash column chromatography using ethyl acetate/
petroleum ether as an eluent. Yield, 98% (373 mg); white crystals;
(t, 2H, 3J ¼ 7.5 Hz, CHCH2CH2), 3.59 (s, 3H, CH3), 3.65 (s, 3H, CH3),
4.44e4.52 (m, 1H, CHCH2CH2), 4.80 (s, 2H, CH2N), 5.16 (s, 2H,
CH2O), 5.57 (d, 1H, 3J ¼ 7.8 Hz, NCHCHCO), 7.02 (d, 2H, 3J ¼ 8.7 Hz,
23
3
mp 103e106 ꢀC; [
a
]
D
þ 18.2 (c 0.283, DMF); IR (KBr)
n
¼ 3379,
Ar-H-20,60), 7.27 (d, 2H, J ¼ 8.7 Hz, Ar-H-30,50), 7.50 (t, 1H,
3291, 3006, 2954, 2896, 2850, 1751, 1732, 1637, 1608, 1535, 1514,
1447, 1437, 1370, 1304, 1248, 1238, 1213, 1171, 1060, 1034, 827, 811,
3J ¼ 7.8 Hz, Ar-H-5), 7.62 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-4), 7.73 (d, 1H,
3J ¼ 7.8 Hz, NCHCHCO), 7.84 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-6), 7.96 (s, 1H,
694 cme1 1H NMR (DMSO-d6)
d
1.96e2.20 (m, 2H, CHCH2CH2), 2.47
Ar-H-2), 8.79 (d, 1H, 3J ¼ 7.5 Hz, CONH), 11.27 (s, 1H, CONHCO); 13
C
(t, 2H, 3J ¼ 7.5 Hz, CHCH2CH2), 3.59 (s, 3H, CH3), 3.65 (s, 3H, CH3),
4.42 (d, 2H, 3J ¼ 5.4 Hz, CH2OH), 4.41e4.52 (m, 1H, CHCH2CH2), 5.03
(t, 1H, 3J ¼ 5.4 Hz, CH2OH), 5.16 (s, 2H, CH2OAr), 6.98 (d, 2H,
NMR (CDCl3) d 27.18 (CH2), 30.24 (CH2), 50.79, 51.93, 52.36, 52.65,
69.56 (CH2O), 102.55, 115.53, 126.29, 126.60, 127.54, 128.96, 129.75,
130,69, 134.07, 137.43, 143.67, 150.84, 158.79 (CO), 163.08 (CO),
166.81 (CO), 172.40 (CO), 173.66 (CO); MS (ESI) m/z (%) ¼ 532
(MNaþ, 8), 510 (MHþ, 100). HRMS for C26H28N3O8: calculated
3J ¼ 8.7 Hz, Ar-H-20,60), 7.24 (d, 2H, J ¼ 8.7 Hz, Ar-H-30,50), 7.50 (t,
3
1H, 3J ¼ 7.8 Hz, Ar-H-5), 7.63 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-4), 7.84 (d, 1H,
3J ¼ 7.8 Hz, Ar-H-6), 7.96 (s, 1H, Ar-H-2), 8.80 (d, 1H, 3J ¼ 7.5 Hz,
510.1876; found 510.1865. HPLC: Phenomenex Luna 5 mm C18
NH); 13C NMR (CDCl3)
d
27.14 (CH2), 30.23 (CH2), 51.99 (CH/CH3),
column (4.6 mm ꢂ 150 mm); mobile phase: 50e80% of methanol in
52.34 (CH/CH3), 52.69 (CH/CH3), 64.96 (CH2O), 69.46 (CH2O),
114.95, 126.20, 126.57, 128.69, 128.94, 130.75, 133.72, 133.91, 137.72,
158.07,166.93 (CO),172.43 (CO),173.72 (CO); MS (ESI) m/z (%) ¼ 438
(MNaþ, 95), 416 (MHþ, 5), 398 (100). HRMS for C22H26NO7: calcu-
lated 416.1709; found 416.1729. Anal. (C22H25NO7) C, H, N.
trifluoroacetic acid (0.1%) in 30 min; flow rate 1.0 mL/min; injection
volume: 20 mL; retention time: 6.967 min (98.75% at 220 nm,
98.89% at 254 nm).
4.6.6.2. (R)-2-(3e((4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)
methyl)phenoxy)methyl)benzamido)
pentanedioic acid (64).
4.6.5. General procedure G. synthesis of compounds 60 and 61
To a stirred solution of 58 or 59 (0.534 g, 1.29 mmol) in
dichloromethane (10 mL), cooled to 0 ꢀC on an ice bath, a solution of
Synthesized according to General procedure E from 62 (100 mg,
0.196 mmol). Yield, 96% (91 mg); white crystals; mp 88e92 ꢀC;
23
[a
]
þ 4.5 (c 0.306, DMF); IR (KBr)
n
¼ 3396, 3048, 2608, 1735,
D
thionyl chloride (326
mL, 4.50 mmol) in dichloromethane (5 mL) was
1686, 1540, 1527, 1508, 1458, 1388, 1350, 1298, 1241, 1176, 1097,
added dropwise. The mixture was allowed to reach room tempera-
ture and stirred for 5 h. Dichloromethane (20 mL) was added and the
organic phase washed with saturated aqueous NaHCO3 solution
(2 ꢂ 15 mL), water (2 ꢂ 15 mL), and brine (2 ꢂ 15 mL), dried over
Na2SO4 and concentrated under reduced pressure.
1040, 1014, 811, 748 cme1 1H NMR (DMSO-d6)
d
1.90e2.16 (m, 2H,
CHCH2CH2), 2.37 (t, 2H, 3J ¼ 7.5 Hz, CHCH2CH2), 4.38e4.46 (m, 1H,
CHCH2CH2), 4.79 (s, 2H, CH2N), 5.15 (s, 2H, CH2O), 5.57 (dd, 1H,
3J ¼ 7.8 Hz, 4J ¼ 2.1 Hz, NCHCHCO), 7.03 (d, 2H, 3J ¼ 8.7 Hz, Ar-H-
20,60), 7.27 (d, 2H, 3J ¼ 8.7 Hz, Ar-H-30,50), 7.50 (t, 1H, 3J ¼ 7.8 Hz, Ar-
H-5), 7.61 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-4), 7.73 (d, 1H, 3J ¼ 7.8 Hz,
NCHCHCO), 7.85 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-6), 7.96 (s, 1H, Ar-H-2),
8.64 (d, 1H, 3J ¼ 7.8 Hz, CONH), 11.27 (d, 1H, 4J ¼ 2.1 Hz, CON-
HCO), 12.35 (br s, 2 ꢂ COOH); MS (ESI) m/z (%) ¼ 504 (MNaþ, 9), 482
(MHþ, 95), 85 (100). HRMS for C24H24N3O8: calculated 482.1563;
found 482.1570. Anal. (C24H23N3O8$0.75H2O) C, H, N. HPLC: Phe-
4.6.5.1. (R)-dimethyl 2-(3e((4-(Chloromethyl)phenoxy)methyl)ben-
zamido)pentanedioate (60). Yield, 94% (0.526 g); white crystals; mp
23
73e77 ꢀC; [
a
]
þ 14.9 (c 0.361, DMF); IR (KBr)
n
¼ 3312, 3048,
D
2956, 2854, 1758, 1734, 1644, 1611, 1586, 1529, 1515, 1438, 1371,
1254, 1210, 1173, 1107, 1034, 986, 836, 750, 691, 662 cme1 1H NMR
(DMSO-d6)
d
1.96e2.20 (m, 2H, CHCH2CH2), 2.47 (t, 2H, 3J ¼ 7.5 Hz,
nomenex Luna 5
phase: 50e80% of methanol in trifluoroacetic acid (0.1%) in 30 min;
flow rate 1.0 mL/min; injection volume: 20 L; retention time:
mm C18 column (4.6 mm ꢂ 150 mm); mobile
CHCH2CH2), 3.59 (s, 3H, CH3), 3.66 (s, 3H, CH3), 4.45e4.52 (m, 1H,
CHCH2CH2), 4.73 (s, 2H, CH2Cl), 5.18 (s, 2H, CH2O), 7.03 (d, 2H,
m
3
3J ¼ 8.7 Hz, Ar-H-20,60), 7.38 (d, 2H, J ¼ 8.7 Hz, Ar-H-30,50), 7.51 (t,
3.235 min (97.17% at 220 nm, 98.46% at 280 nm).
1H, 3J ¼ 7.8 Hz, Ar-H-5), 7.63 (d, 1H, 3J ¼ 7.8 Hz, Ar-H-4), 7.85 (d, 1H,
3J ¼ 7.8 Hz, Ar-H-6), 7.97 (s, 1H, Ar-H-2), 8.80 (d, 1H, 3J ¼ 7.5 Hz,
NH); 13C NMR (CDCl3)
d
27.12 (CH2), 30.24 (CH2), 46.22 (CH2Cl),
Acknowledgement
51.99 (CH/CH3), 52.37 (CH/CH3), 52.69 (CH/CH3), 69.48 (CH2O),
115.07, 126.24, 126.61, 128.97, 130.15, 130.23, 130.76, 133.95, 137.53,
158.60,166.87 (CO),172.40 (CO),173.74 (CO); MS (ESI) m/z (%) ¼ 456
(MNaþ, 20), 434 (MHþ, 40), 107 (100). HRMS for C22H25ClNO6:
calculated 434.1370; found 434.1375. Anal. (C22H24ClNO6) C, H, N.
This work was supported by the EU FP6 Integrated Project EUR-
INTAFAR (Project LSHM-CT-2004-512138) and by the Slovenian
Research Agency (GrantP1-0208). The authors thank Dr. Roger Pain
for critical reading of the manuscript.