M. Miura et al. / Bioorg. Med. Chem. 15 (2007) 160–173
167
room temperature for 12 h. The mixture was partitioned
between AcOEt and H2O and extracted with AcOEt,
and the organic layer was washed with H2O and brine,
dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH = 95:5) to give a colorless
amorphous powder (0.200 g). To a stirred solution of
the compound obtained above (0.190 g) in MeOH
(2.0 mL) was added 10% Pd/C powder (19 mg), and
the mixture was stirred under hydrogen atmosphere at
room temperature for 4 h. The catalyst was filtrated
on Celite and the filtrate was concentrated in vacuo to
(237 mg, 81%): mp 152–153 °C (AcOEt); 1H NMR
(400 MHz, DMSO-d6) d: 0.92 (6H, d, J = 6.3 Hz),
1.35–1.46 (1H, m), 1.59–1.77 (2H, m), 2.84 (3H, s),
3.08 (3H, s), 4.88–5.00 (1H, m), 7.23 (1H, dd,
J = 1.5 Hz, 7.4 Hz), 7.26–7.35 (3H, m), 7.45–7.57 (3H,
m), 7.62 (1H, d, J = 8.3 Hz), 7.69 (1H, dd, J = 1.4 Hz,
7.4 Hz), 7.87 (1H, s), 7.98 (1H, dd, J = 1.5 Hz, 8.1 Hz),
8.02 (1H, s), 8.34 (1H, d, J = 1.4 Hz), 8.78 (1H, d,
J = 8.3 Hz), 10.27 (1H, s), 12.89 (1H, br s); FAB-MS
(m/z): 545 (M+H)+; Anal. Calcd for C30H32N4O6Æ1.2-
H2O: C, 63.64; H, 6.12; N, 9.90. Found: C, 63.59; H,
25
D
6.07; N, 9.66; ½aꢀ +19° (c 0.1, MeOH).
1
give 10 (0.154 g, 35%) as a colorless solid: H NMR
(300 MHz, DMSO-d6) d: 0.88 (3H, d, J = 6.3 Hz), 0.91
(3H, d, J = 6.4 Hz), 1.53–1.62 (1H, m), 1.65–1.81 (2H,
m), 4.38–4.47 (1H, m), 7.20–7.25 (1H, m), 7.27–7.37
(3H, m), 7.47–7.65 (3H, m), 7.71–7.78 (1H, m), 7.88
(1H, br s), 7.97 (1H, dd, J = 2.0 Hz, 8.0 Hz), 8.04 (1H,
br s), 8.27 (1H, d, J = 2.0 Hz), 8.78 (1H, d,
J = 7.7 Hz), 10.16 (1H, s); ESI-MS (m/z): 572 (MꢁH)ꢁ.
5.1.13. Benzyl 2-hydroxy-5-nitrobenzoate (12). To a stir-
red solution of 2-hydroxy-5-nitrobenzoic acid11
(49.8 g, 271 mmol) and KHCO3 (32.5 g, 325 mmol)
in DMF (270 mL) was added benzyl bromide
(38.6 mL, 325 mmol), and the mixture was stirred at
room temperature for 12 h. The mixture was parti-
tioned between AcOEt and 5% NaHCO3 in H2O
and the organic layer was dried over MgSO4, filtered,
and concentrated in vacuo to give 12 (68.6 g, 93%) as
5.1.10. 20-({[3-(Aminocarbonyl)phenyl]amino}carbonyl)-
4-[({3-methyl-(1S)-[(methylamino)carbonyl]butyl}amino)-
carbonyl]biphenyl-2-carboxylic acid (9f). Compound 9f
was synthesized from 10 and methylamineÆHCl accord-
ing to the same procedure as that for 9a. Compound
9f was obtained as a colorless solid (198 mg, 77%): mp
1
a yellow solid: H NMR (300 MHz, DMSO-d6) d: 5.40
(2H, s), 7.19 (1H, d, J = 9.2 Hz), 7.33–7.47 (3H, m),
7.47–7.55 (2H, m), 8.33 (1H, dd, J = 2.9 Hz, 9.2 Hz),
8.54 (1H, d, J = 2.9 Hz), 11.61 (1H, br s); FAB-MS
(m/z): 272 (MꢁH)ꢁ.
1
157–158 °C (AcOEt); H NMR (400 MHz, DMSO-d6)
d: 0.86 (3H, d, J = 6.3 Hz), 0.89 (3H, d, J = 6.4 Hz),
1.48–1.75 (3H, m), 2.58 (3H, d, J = 4.9 Hz), 4.40–4.52
(1H, m), 7.23 (1H, dd, J = 1.5 Hz, 7.4 Hz), 7.26–7.35
(3H, m), 7.45–7.58 (3H, m), 7.63 (1H, d, J = 8.3 Hz),
7.69 (1H, dd, J = 1.5 Hz, 7.3 Hz), 7.82–7.93 (2H, m),
7.96–8.07 (2H, m), 8.36 (1H, d, J = 1.4 Hz), 8.66 (1H,
d, J = 8.3 Hz), 10.28 (1H, s), 12.90 (1H, br s); FAB-
MS (m/z): 531 (M+H)+; Anal. Calcd for C29H30N4
5.1.14. Benzyl 5-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-
benzoate (13). To a stirred solution of 12 (14.9 g,
54.5 mmol) and pyridine (8.8 mL, 109 mmol) in CH2Cl2
(300 mL) was added trifluoromethanesulfonic anhydride
(13.8 mL, 82.0 mmol), and the mixture was stirred at
room temperature for 30 min. The mixture was parti-
tioned between CH2Cl2 and H2O, and the organic layer
was dried over MgSO4, filtered, and concentrated in vac-
uo. The residue was purified by silica gel column chro-
matography (hexane/AcOEt = 9:1) to give 13 (11.2 g,
51%) as a colorless solid: 1H NMR (300 MHz,
DMSO-d6) d: 5.44 (2H, s), 7.35–7.53 (5H, m), 7.92
(1H, d, J = 9.2 Hz), 8.63 (1H, dd, J = 2.8 Hz, 9.2 Hz),
8.73 (1H, d, J = 2.8 Hz).
O6Æ1.0H2O: C, 63.49; H, 5.88; N, 10.21. Found: C,
25
D
63.32; H, 5.97; N, 10.08; ½aꢀ +18° (c 0.1, MeOH).
5.1.11. 20-({[3-(Aminocarbonyl)phenyl]amino}carbonyl)-
4-{[((1S)-carboxy-3-methylbutyl)amino]carbonyl}biphe-
nyl-2-carboxylic acid (9d). Compound 9d was
synthesized from 10 according to the same procedure
as that for 9a without condensation. Compound 9d
was obtained as a colorless solid (237 mg, 78%): mp
5.1.15. 20-Benzyl 2-tert-butyl 4-methyl 40-nitrobiphenyl-
2,20,4-tricarboxylate (14). To a stirred solution of 6
(1.00 g, 2.60 mmol), bis(pinacolato)diboron (726 mg,
2.86 mmol), PPh3 (41 mg, 0.156 mmol), and
PdCl2(PPh3)2 (55 mg, 0.078 mmol), in toluene (30 ml)
was added AcOK (306 mg, 3.12 mmol) at room temper-
ature under an argon atmosphere. The mixture was re-
fluxed overnight, and then 13 (1.05 mg, 2.60 mmol),
Pd(PPh3)4 (150 mg, 0.13 mmol), and 2 mol dmꢁ3aq
Na2CO3 (6.5 ml) were added to the reaction mixture.
The solution was refluxed overnight. The mixture was
extracted with AcOEt and the organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatogra-
phy (hexane/AcOEt = 9:1) to give 14 (951 mg, 74%) as
a colorless solid: 1H NMR (300 MHz, DMSO-d6) d:
1.15 (9H, s), 3.93 (3H, s), 5.05 (2H, s), 7.04–7.11 (2H,
m), 7.20–7.30 (3H, m), 7.33 (1H, d, J = 8.1 Hz), 7.56
(1H, d, J = 8.4 Hz), 8.05 (1H, dd, J = 1.5 Hz, 8.1 Hz),
8.28 (1H, d, J = 1.5 Hz), 8.44 (1H, dd, J = 2.3 Hz,
1
155–157 °C (AcOEt); H NMR (400 MHz, DMSO-d6)
d: 0.88 (3H, d, J = 6.4 Hz), 0.92 (3H, d, J = 6.3 Hz),
1.50–1.63 (1H, m), 1.63–1.86 (2H, m), 4.38–4.52 (1H,
m), 7.23 (1H, d, J = 6.8 Hz), 7.26–7.35 (3H, m), 7.45–
7.57 (3H, m), 7.61 (1H, d, J = 7.4 Hz), 7.69 (1H, d,
J = 5.9 Hz), 7.87 (1H, s), 7.97 (1H, d, J = 7.8 Hz), 8.04
(1H, s), 8.32 (1H, s), 8.80 (1H, d, J = 7.8 Hz), 10.44
(1H, s), 12.70 (1H, br s); FAB-MS (m/z): 518 (M+H)+;
Anal. Calcd for C28H27N3O7Æ1.2H2O: C, 62.38; H,
25
D
5.50; N, 7.79. Found: C, 62.39; H, 5.51; N, 7.64; ½aꢀ
+7° (c 0.1, MeOH).
5.1.12. 20-({[3-(Aminocarbonyl)phenyl]amino}carbonyl)-
4-[({(1S)-[(dimethylamino)carbonyl]-3-methylbutyl}ami-
no)carbonyl]biphenyl-2-carboxylic acid (9g). Compound
9g was synthesized from 10 and dimethylamineÆHCl
according to the same procedure as that for 9a.
Compound 9g was obtained as a colorless solid