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T. Maeda et al. / Bioorg. Med. Chem. 12 (2004) 4351–4360
2c (3.7 g, 11.6 mmol, 81.5% yield): mp 162.8 ꢁC; IR (KBr)
cmꢀ1: 3267, 3047, 2951, 1729, 1632, 1536, 1434, 1281,
962, 771; 1H NMR (CDCl3) d: 3.93 (3H, s, CO2Me), 4.78
(2H, d, J ¼ 6:0 Hz, PhCH2), 7.42–8.38 (11H, m,
arom.H11); EI-MS m=z: 319.12 (M)þ; HR-EI-MS m=z:
(M)þ calcd for C20H17NO3, 319.1208; found, 319.1206.
J ¼ 6:4 Hz, PhCH2), 6.60 (1H, br s, CH2NH), 7.15 (2H,
t, J ¼ 8:4 Hz, arom.H2), 7.43 (2H, d, J ¼ 8:4 Hz,
arom.H2), 7.57 (2H, dd, J ¼ 1:6, 5.6 Hz, arom.H2), 7.61
(2H, d, J ¼ 8:4 Hz, arom.H2), 7.88 (2H, d, J ¼ 8:4 Hz,
arom.H2), 8.02 (2H, d, J ¼ 8:4 Hz, arom.H2); EI-MS
m=z: 363 (M)þ; HR-EI MS m=z: (M)þ calcd for
C22H18NO3F, 363.1271; found, 363.1274.
4.14. 4-[(1-Naphthoylamino)methyl]benzoic acid (3c)
4.18. 4-({[(40-Fluoro[1,10-biphenyl]-4-yl)carbonyl]amino}-
methyl)benzoic acid (3d)
2c (3.0 g, 9.4 mmol) was hydrolyzed with 1 M LiOH
(27 mL, 27 mmol) in a mixture of water (0.5 mL) and
THF (16.5 mL), affording 3c (2.3 g, 7.5 mmol, 78.8%
yield): mp 255.1 ꢁC; IR (KBr) cmꢀ1: 3267, 2562, 1692,
1632, 1578, 1536, 1433, 1286, 950,751; 1H NMR
(CDCl3) d: 4.61 (2H, d, J ¼ 6:0 Hz, PhCH2), 7.50–8.04
(11H, m, arom.H11), 9.16 (1H, t, J ¼ 6:0 Hz, CH2NH),
12.95 (1H, br s, CO2H); EI-MS m=z: 305.11 (M)þ;
HR-EI-MS m=z: (M)þ calcd for C19H15NO3, 305.1052;
found, 305.1066.
2d (1.1 g, 3.1 mmol) was hydrolyzed with 1M LiOH
(13.0 mL, 13.0 mmol) in a mixture of water (0.5 mL) and
THF (17.5 mL), affording 3d (0.9 g, 2.6 mmol, 83%
yield): mp 267.3–269.4 ꢁC; IR (KBr) cmꢀ1: 3292, 3099,
2542, 2341, 1686, 820, 756, 669; 1H NMR (DMSO-d6 d:
4.50 (2H, d, J ¼ 5:6 Hz, PhCH2), 7.23 (2H, d,
J ¼ 7:2 Hz, arom.H2), 7.32 (2H, t, J ¼ 8:8 Hz,
arom.H2), 7.75–7.82 (6H, m, arom.H6), 7.99 (2H, d,
J ¼ 8:0 Hz, arom.H2), 9.09 (1H, br s, CH2NH); EI-MS
m=z: 349 (M)þ; HR-EI-MS m=z: (M)þ calcd for
C21H16NO3F, 349.1114; found, 349.1118.
4.15. N-({4-[(Benzyloxyamino)carbonyl]benzyl}methyl)-
1-naphthamide (4c)
3c (1.0 g, 3.3 mmol) was condensed with O-benzylhydr-
oxylamine hydrochloride (0.5 g, 3.1 mmol) in the pre-
sence of BOP-Cl (0.9 g, 3.5 mmol) and Et3N (0.5 mL,
3.6 mmol) in CH2Cl2 (45 mL), yielding 4c (8.6 g,
4.19. N-(4-{[(Benzyloxy)amino]carbonyl}benzyl)-40-
fluoro[1,10-biphenyl]-4-carboxamide (4d)
3d (1.0 g, 2.9 mmol) was condensed with O-benzylhydr-
oxylamine hydrochloride (0.54 g, 3.4 mmol) in the pre-
sence of BOP-Cl (1.3 g, 5.2 mmol) and Et3N (1.6 mL,
11.4 mmol) and DMF (15 mL) in the usual way, giving
rise to 4d (0.41 g, 0.9 mmol, 40% yield): mp 241.4–
243.7 ꢁC; IR (KBr) cmꢀ1: 3321, 3206, 1634, 1495, 1279,
893, 860, 772; 1H NMR (DMSO-d6) d: 4.55 (2H, d,
J ¼ 5:7 Hz, PhCH2), 4.92 (2H, s, OCH2), 7.29–7.60 (8H,
m, arom.H8), 7.71–7.98 (6H, m, arom.H6), 8.01–8.12
(3H, m, arom.H3), 9.16 (1H, t, J ¼ 5:7 Hz, CH2NH),
11.7 (1H, s, BnONH); FAB-MS m=z: 455 (M+H)þ; HR-
FAB-MS m=z: (M+H)þ calcd for C28H24N2O3F,
455.1771; found, 455.1747.
19.7 mmol, 39.3% yield): mp 198.0 ꢁC; IR (KBr) cmꢀ1
:
3270, 3035, 1643, 1518, 1424, 1304, 1256, 1016, 785, 696;
1H NMR (CDCl3) d: 4.58 (2H, d, J ¼ 6:0 Hz, PhCH2),
4.94 (2H, s, OCH2), 7.33–8.23 (16H, m, arom.H16), 9.14
(1H, t, J ¼ 6:0 Hz, CH2NH), 11.74 (1H, br s, BnONH);
EI-MS m=z: 410.16 (M)þ; HR-EI-MS m=z: (M)þ calcd
for C26H22N2O3, 410.1630; found, 410.1611.
4.16. N-({4-[(Hydroxyamino)carbonyl]benzyl}methyl)-1-
naphthamide (6c)
4c (0.31 g, 0.73 mmol) was subjected to hydrogenolysis
with 10% Pd–C (80 mg) in MeOH (23 mL), furnishing 6c
(0.12 g, 0.37 mmol, 56.0% yield): mp 169.5 ꢁC; IR (KBr)
cmꢀ1: 3302, 1637, 1530, 1388, 1303, 1245, 1154, 1031,
4.20. 40-Fluoro-N-{4-[(hydroxyamino)carbonyl]benzyl}-
[1,10-biphenyl]-4-carboxamide (6d)
1
900, 783; H NMR (CDCl3) d: 4.58 (2H, d, J ¼ 6:0 Hz,
PhCH2), 7.46–8.22 (11H, m, arom.H11), 9.00 (1H, s,
HONH), 9.13 (1H, t, J ¼ 6:0 Hz, CH2NH), 11.19 (1H,
br s, OH); FAB-MS m=z: 321 (M+H)þ; HR-FAB-MS
m=z: (M+H)þ calcd for C19H17N2O3, 321.1239; found,
321.1219.
4d (0.10 g, 0.22 mmol) was subjected to hydrogenolysis
with 10% Pd–C (70 mg) in MeOH (30 mL), yielding 6d
(57 mg, 0.16 mmol, 71% yield): mp (dec) 218.7 ꢁC; IR
(KBr) cmꢀ1: 3267, 3049, 2806, 1880, 1641, 1612, 1537,
1
1514, 1470, 829, 770, 739, 719, 692, 594, 523, 436; H
NMR (DMSO-d6 d: 4.54 (2H, d, J ¼ 5:7 Hz, PhCH2),
7.29–7.44 (4H, m, arom.H4), 7.70–8.00 (8H, m,
arom.H8), 9.14 (1H, br s, CH2NH); FAB-MS m=z: 365
(M+H)þ; HR-FAB-MS m=z: (M+H)þ calcd for
C21H18N2O3F, 365.1301; found, 365.1308.
4.17. Methyl 4-({[(40-fluoro[1,10-biphenyl]-4-yl)car-
bonyl]amino}methyl)benzoate (2d)
40-Fluoro[1,10-biphenyl]-4-carboxylic acid (2.8 g, 13
mmol) was condensed with 1 (2.9 g, 14 mmol) in the
presence of BOP-Cl (4.18 g, 15.6 mmol) and Et3N
(14.4 mL, 104 mmol) in absolute DMF (80 mL) in the
usual way, affording the pure compound 2d (3.6 g,
9.9 mmol, 76% yield): mp 194.6–196.5 ꢁC; IR (KBr)
cmꢀ1: 1720, 1495, 1283, 1240, 1103, 831, 760, 708, 598;
1H NMR (CDCl3) d: 3.91 (3H, s, CO2Me), 4.73 (2H, d,
4.21. Methyl 4-({[(40-methoxy[1,10-biphenyl]-4-yl)car-
bonyl]amino}methyl)benzoate (2e)
40-Methoxy[1,10-biphenyl]-4-carboxylic
8.3 mmol) was condensed with 1 (2.2 g, 10.9 mmol) in
acid
(1.9 g,