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Y. Uto et al. / Bioorg. Med. Chem. 16 (2008) 6042–6053
cuo. The remaining aqueous solution was extracted with
ethyl acetate and the organic layer washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash chromatography to afford (2S)-3-
tert-butoxy-1-(2-nitroimidazolyl)-2-propyl- 40-amino-
benzoate 25 (113 mg, 79.4%). IR (KBr; cmꢀ1): 3337
(NH2), 2963, 1701 (CO), 1605, 1541, 1483, 1365 (imidaz-
olyl-NO2), 1263, 1173, 1098, 804, 767. 1H NMR
(C2D6SO): d 11.55 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H),
7.82 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.08 (s, 1H),
5.46 (m, 1H), 4.90 (dd, J = 7.2 Hz, 1H), 4.65 (dd,
J = 9.2 Hz, 1H), 3.65 (dd, J = 7.4 Hz, 2H), 1.19 (s,
9H). MS (EI) m/z: 362 (M+).
7.82 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.08 (s, 1H),
5.46 (m, 1H), 4.90 (dd, J = 7.2 Hz, 1H), 4.65 (dd,
J = 9.2 Hz, 1H), 3.65 (dd, J = 7.4 Hz, 2H), 1.19 (s,
9H). MS (EI) m/z: 438 (M+).
A mixture of 16 (100 mg, 0.23 mmol), 17 (37.29 mg,
0.27 mmol), and EtOH (10 mL) was refluxed for 24 h.
The product mixture was then evaporated under aspira-
tor vacuum and the residue was purified by silica gel col-
umn chromatography (silica gel 60 N, hexane/ethyl
acetate, 3:2) to give 5 (34 mg, 27.4%) (TX-2036) as a yel-
26
D
low crystals. Mp 186–188 ꢂC; ½aꢁ +63.3ꢂ (c 0.40,
CHCl3), IR (KBr; cmꢀ1): 3337, 2963, 1717, 1659,
1605, 1488, 1365, 1263, 1103, 847, 767, 687; H NMR
1
A mixture of 25 (51.85 mg, 0.14 mmol), 17 (20.72 mg,
0.15 mmol), and EtOH (5 mL) was refluxed for 24 h.
After removal of solvents under aspirator vacuum, the
residue was purified by silica gel column chromatogra-
phy (silica gel 60 N, hexane/ethyl acetate, 3:2) to give
(C2D6SO): d 10.6 (d, J = 13.6 Hz, 1H: NH), 8.03 (d,
J = 13.6 Hz, 1H:N–CH@), 7.85 (d, J = 8.5 Hz, 2H),
7.69 (s, 1H: imidazole), 7.64 (d, J = 8.8 Hz, 2H), 7.29
(d, J = 8.8 Hz, 2H), 7.16 and 7.08 (each d, J = 6.0,
6.4 Hz, each 1H), 7.10 (d, J = 0.8 Hz, 1H), 6.91 (d,
J = 8.8 Hz, 2H), 5.77 (m, 1H), 5.01 (d, J = 12.4 Hz,
1H), 4.84 (dd, J = 9.2 Hz, 1H), 4.36 (dd, J = 10.8 Hz,
1H), 4.29 (dd, J = 11.2 Hz, 1H), 1.24 (s, 9H). Anal.
Calcd for C29H28N4O7: C, 63.96; H, 5.18; N, 10.29.
Found: C, 63.68; H, 5.50; N, 10.41.
44.6 mg (66.6%) of 4 (TX-2031) as yellow crystals, Mp
26
D
130–131 ꢂC. ½aꢁ ꢀ141.0ꢂ (c 0.63, CHCl3); IR (KBr;
cmꢀ1): 3323, 2974, 1717, 1659, 1603, 1541, 1488, 1365,
1
1269, 1183, 1103, 847, 767; H NMR (C2D6SO): d 10.6
(d, 1H), 8.04 (d, J = 13.2 Hz, 1H), 7.86 (d, J = 8.8 Hz,
2H), 7.64 (d, J = 9.2 Hz, 3H), 7.15 (d, J = 5.9 Hz, 1H),
7.09 (d, J = 6.8 Hz, 3H), 5.44 (m, 1H), 4.87 (dd,
J = 13.9 Hz, 1H), 4.65 (dd, J = 14.4 Hz, 1H), 3.63 (dd,
J = 12.8 Hz, 2H), 1.18 (s, 9H). Anal. Calcd for
C23H24N4O7: C, 58.97; H, 5.16; N, 11.96. Found: C,
58.75; H, 5.36; N, 11.74.
4.3.8. Synthesis of 6 (TX-2037). Diisopropylcarbodiim-
ide (ca. 164 mg/200 lL, 1.3 mmol) was added to a solu-
tion of (2S)-p-tert-butylphenoxy-1-(2-nitroimidazolyl)-
2-propanol 207 (159.7 mg, 0.5 mmol), 10 (237.0 mg,
1 mmol),
and
4-dimethylaminopyridine
(18 mg,
0.1 mmol) in acetonitrile (5 mL) and the mixture was
stirred under nitrogen at 30–45 ꢂC for 24 h. It was then
cooled, filtered, and the filtrate was evaporated to dry-
ness. The residue of crude product mixture was dis-
solved in CH2Cl2 (20 mL) and ethyl acetate (10 mL),
washed with 5% sodium bicarbonate and brine, dried
(Na2SO4), and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (ethyl ace-
tate/hexane, 2:3) to afford (2S)-3-p-tert-butylphenoxy-
1-(2-nitroimidazolyl)-2-propyl-40-(trifluoroacetamido)
benzoate, 23 (258 mg, 96.5%). Mp 179–180 ꢂC; IR (KBr;
cmꢀ1): 3337, 3123, 2974, 1717, 1605, 1541, 1493, 1365,
4.3.7. Synthesis of 5 (TX-2036). To a solution of (2R)-p-
tert-butylphenoxy-1-(2-nitroimidazolyl)-2-propanol 97
(159.7 mg, 0.5 mmol), 10 (239 mg, 1 mmol), and 4-
dimethylaminopyridine (14.2 mg, 0.08 mmol) in acetoni-
trile (5 mL) was added diisopropylcarbodiimide (ca.
164 mg/200 lL, 1.3 mmol) and the mixture was stirred
under nitrogen at 35–45 ꢂC for 24 h. After this time
the mixture was cooled, filtered, and the filtrate was
evaporated to dryness. The crude product mixture was
dissolved in CH2Cl2, washed with 5% sodium bicarbon-
ate and brine, dried (Na2SO4), and concentrated in va-
cuo. The crude product was purified by flash
chromatography (ethyl acetate ester/hexane, 2:3) to af-
ford (2R)-3-p-tert-butylphenoxy-1-(2-nitroimidazolyl)-
2-propyl-40-(trifluoroacetamido)benzoate 13 (179.7 mg,
yield: 74.7%), Mp 180–181 ꢂC.
1
1253, 1199, 1157, 1103, 767, 735; H NMR (C2D6SO):
d 11.55 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.82 (d,
J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.08 (s, 1H), 5.46 (m,
1H), 4.90 (dd, J = 7.2 Hz, 1H), 4.65 (dd, J = 9.2 Hz,
1H), 3.65 (dd, J = 7.4 Hz, 2H), 1.19 (s, 9H).
Sodium borohydride (36.8 mg, 1.0 mmol) was added to
a solution of 13 (158.8 mg, 0.297 mmol) in 10 mL of
absolute ethanol, and the mixture was stirred overnight
at room temperture. The solution was then cooled and
quenched by the dropwise addition of water (5 mL).
After removal of the volatile solvent in vacuo, the
remaining aqueous solution was extracted with ethyl
acetate and the organic layer washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue of
crude product was purified by flash chromatography
to afford (2R) ꢀ p-tert-butylphenoxy-1-(2-nitroimidaz-
olyl)-2-propyl-40-aminobenzoate, 16 (114.2 mg, 87.7%).
IR (KBr; cmꢀ1): 3337, 2963, 1701, 1603, 1515, 1490,
1365, 1245, 1170, 1101, 836, 769, 700; 1H NMR
(C2D6SO): d11.55 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H),
Sodium borohydride (39.2 mg, 1.05 mmol) was added to
a solution of 23 (243 mg, 0.45 mmol) in 10 mL of abso-
lute ethanol, and the mixture was stirred for 24 h at
room temperature after the reaction was quenched by
dropwise addition of water (5 mL) and the volatile sol-
vent was removed in vacuo. The remaining aqueous
solution was then extracted with ethyl acetate and the
organic layer was washed with brine, dried (Na2SO4),
and concentrated in vacuo. The residue of crude product
was purified by flash chromatography to afford (2S)-p-
tert-butylphenoxy-1-(2-nitroimidazolyl)-2-propyl-40-
aminobenzoate, 26 (188.2 mg, 95.4%). Mp 110–111 ꢂC;
IR (KBr; cmꢀ1): 3348, 2969, 1701, 1625, 1602, 1514,
1489, 1364, 1268, 1171, 1100, 837, 768. 1H NMR
(C2D6SO): d 11.55 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H),