K.S. Lim et al. / European Journal of Medicinal Chemistry 68 (2013) 233e243
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4.1.41. 4-Amino-3-bromo-5-methoxy-phenol (49)
3H), 1.83 (m, 3H), 1.52 (s, 3H), 0.95e1.00 (m, 12H), 0.20 (s, 6H);
LRMS m/z (FAB) 823 (M þ H).
The titled compound was prepared from 46 by following the
procedure for the synthesis of 48 as a white solid in 28% yield.
1H NMR (300 MHz, CDCl3)
J ¼ 2.5 Hz), 3.81 (s, 3H).
d
6.56 (d, 1H, J ¼ 2.5 Hz), 6.36 (d, 1H,
4.1.48. Compound 56
The titled compound was prepared from 22 by following the
general procedure for RTX carbonates as a white solid in 93% yield.
4.1.42. 4-Amino-3-iodo-5-methoxy-phenol (50)
1H NMR (300 MHz, CDCl3)
d 7.47 (s, 1H, Ar), 7.35e7.38 (m, 2H),
The titled compound was prepared from 47 by following the
procedure for the synthesis of 48 as a white solid in 20% yield.
7.20e7.31 (m, 3H), 7.19 (d, 1H, J ¼ 2.8 Hz), 6.70 (d, 1H, J ¼ 2.8 Hz),
6.02 (s, 1H), 4.63e4.75 (m, 4H), 4.27 (d, 1H, J ¼ 2.6 Hz), 3.77 (s, 3H,
OCH3), 3.21 (s, 2H), 3.16 (bs, 2H), 2.55e2.65 (m, 2H), 2.02e2.30 (m,
3H), 1.83 (m, 3H), 1.52 (s, 3H), 0.95e1.00 (m, 12H), 0.20 (s, 6H);
LRMS m/z (FAB) 871 (M þ H).
1H NMR (300 MHz, CDCl3)
d
6.76 (d, 1H, J ¼ 2.4 Hz), 6.40 (d, 1H,
J ¼ 2.5 Hz), 3.80 (s, 3H).
4.1.43. Compound 52
To a stirred solution of ROPA 51 (50 mg, 0.11 mmol) in CH2Cl2
(8 mL) was added 4-nitrophenyl chloroformate (86 mg, 0.43 mmol)
followed by triethylamine (0.02 mL, 0.16 mmol) at 0 ꢀC. After stir-
ring overnight at room temperature, the reaction mixture was
diluted with EtOAc. The organic layer was washed with saturated
NaHCO3, water and brine, and dried over Na2SO4. The suspension
was filtered and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography to afford 52 (60 mg, 87%)
as a white solid.
4.1.49. Compound 57
To a cooled solution of 53 (14 mg, 0.018 mmol) in THF (1 mL) at
0
ꢀC was added tetrabutylammonium fluoride (0.027 mL,
0.027 mmol) slowly. After stirring 2 h at room temperature, the
reaction mixture was quenched with saturated NaHCO3 solution.
The organic layer was washed with water and brine and dried over
Na2SO4. The suspension was filtered and the filtrate was concen-
trated in vacuo. The residue was purified by column chromatog-
raphy to afford 57 as a white solid (8 mg, 68%).
1H NMR (400 MHz, CDCl3)
d
8.29 (d, 2H, J ¼ 9.2 Hz), 7.48 (s, 1H,
1H NMR (500 MHz, CDCl3)
d 7.44 (s, 1H, Ar), 7.33e7.35 (m, 2H),
Ar), 7.33e7.35 (m, 4H), 7.19e7.27 (m, 3H), 6.05 (s, 1H), 4.62e4.72
(m, 4H), 4.27 (d, 1H, J ¼ 2.6 Hz), 3.21 (s, 2H), 3.16 (bs, 2H), 2.54e2.66
(m, 2H), 2.12e2.30 (m, 3H), 1.83 (m, 3H), 1.51 (s, 3H), 0.96 (d, 3H,
J ¼ 7.1 Hz); LRMS m/z (FAB) 630 (M þ H).
7.19e7.27 (m, 3H), 6.65 (dd, 1H, J ¼ 2.5, 10.6 Hz), 6.55 (m, 1H), 6.00
(s, 1H), 5.25 (b, 1H), 4.63e4.72 (m, 4H), 4.25 (d, 1H, J ¼ 2.6 Hz), 3.88
(s, 3H, OCH3), 3.19 (s, 2H), 3.13 (bs, 2H), 2.53e2.60 (m, 2H), 2.02e
2.27 (m, 3H), 1.81 (s, 3H), 1.51 (s, 3H), 0.95 (d, 3H, J ¼ 7.1 Hz); LRMS
m/z (FAB) 649 (M þ H), HRMS m/z (FAB) calculated 649.2449
(M þ H), found 649.2427.
4.1.44. General procedure for RTX carbonates
To a stirred solution of 52 (20 mg, 0.032 mmol) in CH2Cl2 (5 mL)
was added phenol (0.064 mmol, 2 eq.) and DMAP (4 mg,
0.035 mmol). After stirring overnight at room temperature, the
reaction mixture was diluted with EtOAc. The organic layer was
washed with saturated NaHCO3, water and brine, and dried over
Na2SO4. The suspension was filtered and the filtrate was concen-
trated in vacuo. The residue was purified by column chromatog-
raphy to afford the final carbonate.
4.1.50. Compound 58
The titled compound was prepared from 54 by following the
procedure for the synthesis of 57 as a white solid in 63% yield.
1H NMR (500 MHz, CDCl3)
d 7.44 (s,1H), 7.33e7.35 (m, 2H), 7.19e
7.27 (m, 3H), 6.82 (d, 1H, J ¼ 2.6 Hz), 6.65 (d, 1H, J ¼ 2.6 Hz), 6.00 (s,
1H), 5.70 (b, 1H), 4.63e4.73 (m, 4H), 4.24 (d, 1H, J ¼ 2.6 Hz), 3.88 (s,
3H, OCH3), 3.19 (s, 2H), 3.13 (bs, 2H), 2.54e2.61 (m, 2H), 2.00e2.27
(m, 4H), 1.81 (s, 3H), 1.50 (s, 3H), 0.95 (d, 3H, J ¼ 7.1 Hz); LRMS m/z
(FAB) 665 (M þ H), HRMS m/z (FAB) calculated 665.2154 (M þ H),
found 665.2149.
4.1.45. Compound 53
The titled compound was prepared from 19 by following the
general procedure for RTX carbonates as a white solid in 92% yield.
1H NMR (300 MHz, CDCl3)
d
7.47 (s, 1H, Ar), 7.35e7.38 (m, 2H),
4.1.51. Compound 59
7.20e7.31 (m, 3H), 6.60 (dd, 1H, J ¼ 2.8, 10.4 Hz), 6.52 (m, 1H), 6.02
(s, 1H), 4.64e4.76 (m, 4H), 4.27 (d, 1H, J ¼ 2.6 Hz), 3.79 (s, 3H,
OCH3), 3.21 (s, 2H), 3.16 (bs, 2H), 2.55e2.65 (m, 2H), 2.02e2.30 (m,
3H),1.83 (m, 3H),1.52 (s, 3H), 0.95e1.00 (m,12H), 0.13 (s, 6H); LRMS
m/z (FAB) 763 (M þ H).
The titled compound was prepared from 55 by following the
procedure for the synthesis of 57 as a white solid in 67% yield.
1H NMR (500 MHz, CDCl3)
d 7.44 (s, 1H), 7.33e7.35 (m, 2H), 7.19e
7.27 (m, 3H), 6.97 (d,1H, J ¼ 2.6 Hz), 6.69(d,1H, J ¼ 2.6 Hz), 6.00 (s,1H),
5.79 (b, 1H), 4.63e4.73 (m, 4H), 4.25 (d, 1H, J ¼ 2.6 Hz), 3.88 (s, 3H,
OCH3), 3.19 (s, 2H), 3.13 (bs, 2H), 2.54e2.61 (m, 2H), 2.00e2.27 (m,
4H), 1.81 (s, 3H), 1.50 (s, 3H), 0.95 (d, 3H, J ¼ 7.1 Hz); LRMS m/z (FAB)
709 (M þ H), HRMS m/z (FAB) calculated 711.1636, found 709.1639.
4.1.46. Compound 54
The titled compound was prepared from 20 by following the
general procedure for RTX carbonates as a white solid in 71% yield.
1H NMR (300 MHz, CDCl3)
d
7.47 (s, 1H, Ar), 7.35e7.38 (m, 2H),
4.1.52. Compound 60
7.20e7.31 (m, 3H), 6.84 (d, 1H, J ¼ 2.8 Hz), 6.63 (d, 1H, J ¼ 2.8 Hz),
6.02 (s, 1H), 4.64e4.76 (m, 4H), 4.27 (d, 1H, J ¼ 2.6 Hz), 3.79 (s, 3H,
OCH3), 3.21 (s, 2H), 3.16 (bs, 2H), 2.55e2.65 (m, 2H), 2.02e2.30 (m,
3H), 1.83 (m, 3H), 1.52 (s, 3H), 0.95e1.00 (m, 12H), 0.20 (s, 6H);
LRMS m/z (FAB) 779 (M þ H).
The titled compound was prepared from 56 by following the
procedure for the synthesis of 57 as a white solid in 49% yield.
1H NMR (500 MHz, CDCl3)
d 7.44 (s,1H), 7.33e7.35 (m, 2H), 7.19e
7.27 (m, 3H), 7.14 (d, 1H, J ¼ 2.6 Hz), 6.71 (d, 1H, J ¼ 2.6 Hz), 6.00 (s,
1H), 5.97 (b, 1H), 4.63e4.73 (m, 4H), 4.25 (d, 1H, J ¼ 2.6 Hz), 3.86 (s,
3H, OCH3), 3.19 (s, 2H), 3.13 (bs, 2H), 2.54e2.61 (m, 2H), 2.00e2.27
(m, 4H), 1.81 (s, 3H), 1.50 (s, 3H), 0.95 (d, 3H, J ¼ 7.1 Hz); LRMS m/z
(FAB) 757 (M þ H), HRMS m/z (FAB) calculated 757.1510, found
757.1495.
4.1.47. Compound 55
The titled compound was prepared from 21 by following the
general procedure for RTX carbonates as a white solid in 66% yield.
1H NMR (300 MHz, CDCl3)
d 7.47 (s, 1H, Ar), 7.35e7.38 (m, 2H),
7.20e7.31 (m, 3H), 6.99 (d, 1H, J ¼ 2.8 Hz), 6.67 (d, 1H, J ¼ 2.8 Hz),
6.02 (s, 1H), 4.64e4.76 (m, 4H), 4.27 (d, 1H, J ¼ 2.6 Hz), 3.79 (s, 3H,
OCH3), 3.21 (s, 2H), 3.16 (bs, 2H), 2.55e2.65 (m, 2H), 2.02e2.30 (m,
4.1.53. Compound 61
The titled compound was prepared from 31 by following the
general procedure for RTX carbonates as a white solid in 67% yield.