C. Gambacorti-Passerini, L. Scapozza, J. Yli-Kauhaluoma, et al.
MED
gene (2.0 mL, 20% in toluene, 4 equiv) was added, and the reac-
tion mixture was stirred at 08C for 15 min. The CH2Cl2 phase was
separated, dried (Na2SO4) and evaporated in vacuo. CH2Cl2 (5 mL)
and 4-(2-morpholino-4-ylethoxy)phenylamine (0.20 g, 0.89 mmol,
0.89 equiv) was added to the solid, and the resulting reaction mix-
ture was stirred at RT for 24 h. The reaction mixture was filtered,
and the crude product was purified by flash SiO2 column chroma-
tography (Biotage MPLC, CHCl3/MeOH, 4:1) to give a white solid
MS (438.17): m/z 439.2 [M+H]+, 461.1 [M+Na]+, tR =24.2 min,
purity >99%. (method A).
1-[4-(Benzyloxy)phenyl]-3-(1-nicotinoylindolin-5-yl)urea (21):
A
solution of 4-(benzyloxy)phenyl isocyanate (0.059 g, 0.26 mmol)
and compound 52 (0.063 g, 0.26 mmol) in CH2Cl2 (6 mL) was stirred
at RT for 18 h. The reaction mixture was filtered, and the solid was
washed with a small amount of CH2Cl2. The crude product was pu-
rified by flash SiO2 column chromatography (Biotage MPLC, CHCl3/
MeOH, 1:0!10:1) to give a pale-yellow solid (compound 21;
1
(compound 12; 0.08 g, 18% yield). H NMR (300 MHz, [D6]DMSO):
d=8.75 (s, 1H), 8.63 (s, 1H), 7.77 (d, 1H, J=8.4 Hz), 7.43 (d, 2H, J=
8.3 Hz), 7.36 (d, 2H, J=8.9 Hz), 6.88 (d, 2H, J=8.9 Hz), 6.63 (s, 1H),
4.04 (t, 2H, J=5.8 Hz), 3.72 (s, 3H), 3.57 (t, 4H, J=4.6 Hz), 2.66 (t,
2H, J=5.7 Hz), 2.46 ppm (t, 4H, J=4.6 Hz); 13C NMR (75 MHz,
[D6]DMSO): d=153.8, 151.9, 146.9, 138.9, 132.5, 132.4, 131.7, 128.6,
126.4, 120.1, 114.7, 94.7, 66.2, 65.5, 57.1, 53.6, 35.5 ppm; LC–MS
(455.17): m/z 456.2 [M+H]+, 478.2 [M+Na]+; tR =18.9 min, purity
>99% (method A).
1
0.062 g, 51% yield), H NMR (300 MHz, [D6]DMSO): d=8.79 (s, 1H),
8.70 (dd, 1H, J=4.7, 1.4 Hz), 8.59 (s, 1H), 8.45 (s, 1H), 8.02 (s, 2H),
7.58–7.27 (m, 9H), 7.19 (s, 1H), 7.00–6.86 (m, 2H), 5.06 (s, 2H), 4.02
(t, 2H, J=7.8 Hz), 3.08 ppm (t, 2H, J=8.2 Hz); 13C NMR (75 MHz,
[D6]DMSO): d=165.2, 153.4, 152.7, 150.7, 147.7, 137.3, 136.9, 136.4,
134.7, 133.3, 133.0, 128.4, 127.7, 127.6, 123.5, 119.9, 117.0, 116.5,
115.0, 69.4, 50.5, 28.1 ppm; LC–MS (464.18): m/z 465.2 [M+H]+;
tR =15.2 min, purity >99% (method B).
1-[4-(Benzyloxy)phenyl]-3-[3-(4-chlorophenyl)-1-phenyl-1H-pyra-
zol-5-yl]urea (16):
A
solution of compound 41 (0.083 g,
4-[3-[4-(Benzyloxy)phenyl]ureido]-N-phenylbenzamide (22): A so-
lution of 4-(benzyloxy)phenyl isocyanate (0.25 g, 1.1 mmol,
1.1 equiv) and compound 54 (0.21 g, 1.0 mmol) in THF (10 mL) was
stirred at RT for 12 h. The solvent was evaporated in vacuo, and
the solid residue was washed with a mixture of cold n-hexane and
THF (1:1, 2ꢃ5 mL) and filtered. The crude product was recrystal-
lized from a mixture of n-hexane and THF (2:1) to give a white
solid (compound 22; 0.37 g, 85% yield). 1H NMR (300 MHz,
[D6]DMSO): d=10.1 (brs, 1H), 8.95 (brs, 1H), 8.61(brs, 1H), 7.94–
6.92 (m, 18H), 5.1 ppm (s, 2H); 13C NMR (75 MHz, [D6]DMSO): d=
165.0, 153.7, 152.5, 143.1, 139.4, 137.3, 132.6, 128.7, 128.5, 128.4,
127.7, 127.6, 123.3, 120.3, 120.2, 119.8, 117.0, 116.7, 115.0,
69.4 ppm; LC–MS (437.17) m/z 438.3 [M+H]+, 460.2 [M+Na]+;
tR =27.7 min, purity 97% (method A).
0.31 mmol) and 4-(benzyloxy)phenyl isocyanate (0.069 g,
0.31 mmol) in 1,4-dioxane (3 mL) was irradiated under mw at 708C
for 120 min and stirred at RT for 16 h. The reaction mixture was
evaporated in vacuo, and the crude product was purified by flash
SiO2 column chromatography (Biotage MPLC, n-hexane/EtOAc,
4:1!1:1) to give a white solid (compound 16; 0.073 g, 48% yield).
1H NMR (300 MHz, [D6]DMSO); H NMR (300 MHz, [D6]DMSO): d=
1
8.88 (brs, 1H), 8.49 (brs, 1H), 7.87 (d, 2H, J=8.7 Hz), 7.77 (d, 2H,
J=8.7 Hz), 7.68–7.27 (m, 12H), 6.97–6.88 (m, 3H), 5.05 ppm (s, 2H);
13C NMR (75 MHz, [D6]DMSO): d=153.7, 151.7, 149.0, 138.9, 137.3,
132.5, 132.3, 132.0, 129.4, 128.7, 128.4, 128.0, 127.7, 127.6, 126.8,
124.7, 120.0, 115.0, 96.1, 69.4 ppm; LC–MS (494.15): m/z 495.1 [M+
H]+, tR =19.4 min, purity 98% (method B).
1-[4-(Benzyloxy)phenyl]-3-[3-(2-chlorophenyl)-1-phenyl-1H-pyra-
zol-5-yl]urea (17): Following the procedure for compound 16,
urea derivative 17 was synthesized from a solution of 3-(2-chloro-
phenyl)-1-phenyl-1H-pyrazol-5-ylamine (0.10 g, 0.37 mmol) and 4-
(benzyloxy)phenyl isocyanate (0.084 g, 0.37 mmol) in THF (4 mL),
which was irradiated under mw at 708C for 60 min and stirred at
RT for 21 h. The crude product was recrystallized from THF and
washed with n-hexane to give a white solid (compound 17;
0.074 g, 40% yield). 1H NMR (300 MHz, [D6]DMSO): d=8.91 (brs,
1H), 8.52 (brs, 1H), 7.88–7.84 (m, 1H), 7.67–7.29 (m, 15H), 6.98 (s,
1H), 6.93 (d, 2H, J=9.0 Hz), 5.05 ppm (s, 2H); 13C NMR (75 MHz,
[D6]DMSO): d=153.7, 151.6, 147.9, 138.1, 138.0, 137.2, 132.5, 131.8,
131.1, 130.3, 129.4, 128.4, 128.0, 127.7, 127.6, 127.3, 124.6, 120.0,
115.0, 99.3, 69.4 ppm; LC–MS (494.15): m/z 495.1 [M+H]+; tR =
18.8 min, purity 98% (method B).
[5-(4-Chlorophenyl)-2-methyl-2H-pyrazol-3-yl]carbamic
acid
2,2,2-trichloroethyl ester (35): A 2m solution of NaOH in H2O
(8.0 mL, 16 mmol, 7.5 equiv) was added to a solution of 3-(4-chlor-
ophenyl)-1-methyl-1H-pyrazol-5-ylamine (0.48 g, 2.1 mmol) in
EtOAc (8 mL) at 08C, and the resulting mixture was stirred at 08C
for 30 min. 2,2,2-Trichloroethyl chloroformate (0.54 mL, 3.8 mmol,
1.8 equiv) was added portionwise at 08C over a period of 1 h to
this mixture, and the resulting mixture was stirred at RT for 2 h.
The aqueous layer was extracted with EtOAc (2ꢃ20 mL). The com-
bined organic layers were washed with brine (2ꢃ20 mL), dried
(Na2SO4), filtered and evaporated in vacuo. The crude product was
purified by flash SiO2 column chromatography (n-hexane/EtOAc,
1:0!2:1) to give a white solid (compound 35; 0.66 g, 81% yield);
1
mp: 1368C; H NMR (300 MHz, CDCl3): d=7.67 (2H, d, J=8.4 Hz),
7.34 (2H, d, J=6.9 Hz), 6.86 (1H, s), 6.49 (1H, s), 4.85 (2H, s),
3.81 ppm (3H, s); 13C NMR (75 MHz, CDCl3): d=149.2, 135.5, 133.8,
131.8, 129.0, 126.8, 97.8, 95.0, 75.3, 35.9, 29.9 ppm; IR (KBr): n˜ =
3293, 3214, 2955, 1749, 1714 cmꢁ1
.
N-[4-[3-[4-(Benzyloxy)phenyl]ureido]phenyl]nicotinamide
(20):
Urea derivative 20 was synthesized from a solution of 37 (0.10 g,
0.49 mmol, 1.1 equiv) and 4-(benzyloxy)phenyl isocyanate (0.10 g,
0.44 mmol) in THF (11 mL), which was stirred at RT for 18 h. The re-
action mixture was filtered, and the crude product was purified by
flash SiO2 column chromatography (Biotage MPLC, CHCl3/MeOH,
1:0!10:1) to give a white solid (compound 20; 0.080 g, 41%
yield). 1H NMR (300 MHz, [D6]DMSO): d=10.34 (s, 1H), 9.10 (dd,
1H, J=2.2, 0.7 Hz), 8.75 (dd, 1H, J=4.8, 1.6 Hz), 8.59 (brs, 1H), 8.48
(brs, 1H), 8.28 (dt, 1H, J=8.0, 2.2 Hz), 7.66 (d, 2H, J=9.0 Hz), 7.56
(ddd, 1H, J=8.0, 4.9, 0.8 Hz), 7.47–7.29 (m, 9H), 6.94 (d, 2H, J=
9.1 Hz), 5.06 ppm (s, 2H); 13C NMR (75 MHz, [D6]DMSO): d=163.6,
153.4, 152.7, 152.0, 148.6, 137.3, 136.1, 135.3, 133.0, 132.9, 130.6,
128.4, 127.7, 127.6, 123.5, 121.1, 119.9, 118.3, 115.0, 69.4 ppm; LC–
N-(4-Nitrophenyl)nicotinamide (36): A mixture of nicotinoyl chlo-
ride hydrochloride (1.9 g, 11 mmol, 1.5 equiv), pyridine (1.3 mL,
16 mmol, 2.3 equiv) and CH2Cl2 (20 mL) was stirred at 08C for
30 min. 4-Nitroaniline (1.0 g, 7.2 mmol) was added to the mixture,
which was slowly warmed to RT and then stirred at RT for 16 h.
The solvents were removed, and the crude product was successive-
ly washed with warm H2O and recrystallized from MeOH to give a
1
yellow solid (compound 36; 0.59 g, 33% yield). H NMR (300 MHz,
[D6]DMSO): d=11.09 (s, 1H), 9.19 (s, 1H), 8.91–8.80 (m, 1H), 8.43
(d, J=8.0 Hz, 1H), 8.29 (d, J=9.2 Hz, 2H), 8.07 (d, J=9.3 Hz, 2H),
7.68 ppm (dd, J=7.9, 5.0 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO):
1690
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1680 – 1692