244
F.-C. Favre-Besse et al. / European Journal of Medicinal Chemistry 78 (2014) 236e247
0
purified by preparative HPLC gradient P2. Compound was the first
(dd, J ¼ 8.6 Hz, J ¼ 1.7 Hz, 1H, H5 ); 7.06 (s, 1H, H8); 6.87 (s, 1H, H6);
eluted and obtained as a violet powder in 3% yield (25 mg). 1H NMR
4.00 (s, 3H, H7 ). 13C NMR (126 MHz, DMSO):
d
181.4 (C4); 153.5 (C7);
0
0
0
(500 MHz, DMSO):
d
15.36 (s, 1H, NH); 7.76 (d, J ¼ 8.5 Hz, 1H, H6’);
153.1 (C2); 148.1 (C2 ); 142.8 (C5); 136.3 (C9); 131.1 (C1 ); 129.9 (C3);
0
0
0
0
7.75 (dd, J ¼ 10.3 Hz, J ¼ 1.7 Hz, 1H, H3’); 7.64 (dd, J ¼ 8.5 Hz,
124.1 (C5 ); 123.0 (C1); 116.9 (C6 ); 116.3 (C4 ); 114.6 (C3 ); 113.5 (C8);
0
0
J ¼ 1.7 Hz, 1H, H5 ); 7.29 (s, 1H, H1); 7.08 (d, J ¼ 1.3 Hz, 1H, H6); 6.84
112.1 (C6); 111.8 (C10); 56.6 (C7 ). Elemental analysis found (calcd.)
(d, J ¼ 1.3 Hz, 1H, H8). 13C NMR (126 MHz, DMSO):
d
180.8 (C4);
(þNaCl; þ3H3Oþ): C 30.48 (30.56); H 3.31 (3.29); N 6.27 (6.12); S
9.57 (9.41). HPLC (Gradient A) tR ¼ 10.53 min. MS (ESI)ꢁ: m/z 530.1
[M ꢁ H]ꢁ. UV vis lmax ¼ 543 nm.
0
0
0
156.8 (C7); 154.6 (C2); 150.7 (C3 ); 146.3 (C5 ); 145.4 (C5); 140.5 (C6 );
0
0
134.6 (C9); 134.1 (C1 ); 130.5 (C3); 124.7 (C1); 123.5 (C2 ); 117.2 (C8);
0
115.1 (C6); 111.2 (C10); 89.3 (C4 ). Elemental analysis found (calc)
(þNaCl; þ3H3Oþ): C 28.61 (28.93); H 2.58 (2.66); N 6.09 (6.10).
HPLC (Gradient A) tR ¼ 10.61 min. MS (ESI)ꢁ: m/z 565.9 [M ꢁ H]ꢁ.
UV vis lmax ¼ 536 nm.
4.2.3.23. (E)-5-Ammonio-3-(2-(4-bromo-2,6-dimethylphenyl)hydra-
zono)-4-oxo-3,4-dihydronaphthalene-2,7-disulfonate, 4p (LSP9-
2125). Following the general procedure B, corresponding diazo-
nium salt (1.4 mmol) was added to 5-Amino-4-hydroxy-
naphthalene-2,7-disulfonic acid monosodium salt (445 mg,
1.3 mmol). Compound was obtained as a purple powder in 24%
Compound 16l was the second eluted in the purification of 4l
and obtained as a blue powder in 5% yield (42 mg). 1H NMR
(500 MHz, DMSO):
d
10.53 (s, 1H, NH); 10.30 (s, 1H, NH); 7.90 (dd,
00
yield (180 mg). 1H NMR (500 MHz, DMSO):
d 16.31 (s, 1H, NH); 7.33
J ¼ 10 Hz, J ¼ 1.6 Hz, 1H, H3 ); 7.85 (dd, J ¼ 10.4 Hz, J ¼ 1.4 Hz, 1H,
0
00
0
H3 ); 7.81 (t, J ¼ 8.4 Hz, 1H, H6 ); 7.80 (t, J ¼ 8.3 Hz, 1H, H6 ); 7.73 (dd,
0
0
(s, 2H, H3 , H5 ); 7.31 (s,1H, H1); 7.04 (s,1H, H6); 6.87 (s, 1H, H8); 2.55
00
(s, 6H, H7 ). 13C NMR (126 MHz, DMSO):
d 181.0 (C4); 153.5 (C7);
J ¼ 8.6 Hz, J ¼ 1.4 Hz, 1H, H5 ); 7.70 (dd, J ¼ 8.6 Hz, J ¼ 1.4 Hz, 1H,
0
H5 ); 7.47 (s, 1H, H6); 7.41 (s, 1H, H8). 13C NMR (126 MHz, DMSO):
0
0
0
0
153.0 (C2); 142.7 (C5); 138.0 (C1 ); 136.9 (C9); 131.6 (C3 eC5 ); 129.8
(C3); 122.3 (C1); 116.7 (C2 eC6 ); 113.1 (C8); 112.1 (C6); 111.6 (C10);
106.8 (C4 ); 19.5 (C7 ). Elemental analysis found (calcd.)
(þNaCl; þ2H3Oþ): C 33.49 (33.42); H 3.47 (3.26); N 6.16 (6.48); S
9.76 (9.88). HPLC (Gradient A) tR ¼ 11.96 min. MS (ESI)ꢁ: m/z 530.0
[M ꢁ H]ꢁ. UV vis lmax ¼ 523 nm.
d
180.7; 169.2; 154.7; 146.4; 145.3; 140.6; 140.3; 134.5; 134.0;
0
0
130.5; 129.0; 125.4; 124.5; 123.4; 122.5; 120.0; 119.1; 117.1; 115.0;
109.7; 96.2 HPLC (Gradient A) tR ¼ 14.11 min. MS (ESI)ꢁ: m/z 813.8
[M ꢁ H]ꢁ. UV vis lmax ¼ 600 nm.
0
0
4.2.3.20. (E)-5-Ammonio-3-(2-(4-iodo-2-(trifluoromethyl)phenyl)
hydrazono)-4-oxo-3,4-dihydronaphthalene-2,7-disulfonate,
4m
4.2.3.24. 5d LSP9-3024 and 5b -LSP9-3088. NaOH (20 g, 0.5 mol)
was dissolved in 60 mL of water. 4-Bromo-2-fluoroaniline (19 g,
0.1 mol), sodium formate (6.8 g, 0.1 mol), cetyl trimethy-
lammonium bromide (CTAB) (4 g, 0.01 mol) and palladium on
activated charcoal (2 g) were added to the solution. The reaction
mixture was stirred under reflux for 4 h. Afterwards, another
batch of sodium acetate (6.8 g, 0.1 mol), was added to the so-
lution. The reaction mixture was heated under reflux for another
20 h. After cooling down to room temperature, the reaction
mixture was filtered and the residual solid washed with EtOAc
(500 mL). This layer was filtered to remove salts. Solvents were
removed under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel (Cyclohexane/
EtOAc: 70/30). The first eluted product was 3,30-difluor-
obiphenyl-4,40-diamine (5d), followed by 2-fluorobenzidine and
benzidine 5b).
(LSP9-2119). Following the general procedure B, corresponding
diazonium salt (3.7 mmol) was added to 5-Amino-4-
hydroxynaphthalene-2,7-disulfonic acid (1130 mg, 3.3 mmol). The
crude product was purified by preparative HPLC gradient P2.
Compound was the first eluted and obtained as a dark blue powder
in 2% yield (40 mg). 1H NMR (500 MHz, DMSO):
d
11.05 (brs, 1H,
NH); 8.00 (m, 3H, H3’, H5’, H6’); 7.43 (s, 1H, H1); 7.18 (s, 1H, H6); 7.00
(s, 1H, H8). 13C NMR (126 MHz, DMSO):
d
172.3 (C4); 150.3 (C7);
0
0
0
150.2 (C2); 145.2 (C5 ); 143.8 (C1 ); 142.1 (C5); 136.2 (C9); 134.1 (C3 );
0
0
0
125.8 (C3); 125.1 (C6 eC7 ); 120.3 (C1); 117.2 (C8); 115.2 (C2 ); 113.6
0
(C6); 110.1 (C10); 91.5 (C4 ). HPLC (Gradient A) tR ¼ 12.38 min. MS
(ESI)ꢁ: m/z 615.9 [M ꢁ H]ꢁ. UV vis lmax ¼ 521 nm.
4.2.3.21. (E)-5-Ammonio-3-(2-(4-bromo-2,3,5-trifluoro-6-
hydroxyphenyl)hydrazono)-4-oxo-3,4-dihydronaphthalene-2,7-
disulfonate, 4n (LSP9-3032). Following the general procedure B,
corresponding diazonium salt (1.4 mmol) was added to 5-Amino-4-
hydroxynaphthalene-2,7-disulfonic acid (410 mg, 1.2 mmol) in
10 mL of H2O. The crude product was purified by preparative HPLC
using gradient P2. Compound was obtained as a dark blue solid in
3,30-Difluoro-[1,10-biphenyl]-4,40-diamine 5d was obtained as
an orange powder in 24% yield (2.62 g) 1H NMR (500 MHz, CD3CN):
0
d
7.20 (dd, J ¼ 13 Hz, J ¼ 2 Hz, 2H, H2, H2 ); 7.14 (dd, J ¼ 8.2 Hz,
0
0
J ¼ 2 Hz, 2H, H6, H6 ); 6.82 (t, J ¼ 8.8 Hz, 2H, H5, H5 ); 4.19 (brs, 4H,
2 ꢃ NH2). 13C NMR (126 MHz, CD3CN):
d
152.7 (d, J ¼ 236.8 Hz, C3,
74% yield (510 mg). 1H NMR (500 MHz, DMSO):
d 15.55 (s, 1H, NH);
0
0
0
10.72 (s, 1H, OH); 7.28 (s, 1H, H1); 7.14 (s, 1H, H6); 6.9 (s, 1H, H8). 13
C
C3 ); 135.5 (d, J ¼ 13.4 Hz, C4, C4 ); 130.9 (d, J ¼ 6.3 Hz, C1, C1 ); 123.1
0
0
(d, J ¼ 2.4 Hz, C6, C6 ); 117.9 (d, J ¼ 4.4 Hz, C5, C5 ); 113.6 (d,
NMR (126 MHz, DMSO):
d 182.4 (C4); 154.5 (C7); 154.1 (C2); 145.5
0
J ¼ 19.5 Hz, C2, C2 ).
0
0
0
0
(C5 ); 140.8 (C5); 140.1 (C3 ); 136.5 (C2 ); 135.9 (C9); 134.4 (C6 ); 129.8
Benzidine 5b was obtained as an orange powder in 10% yield
0
(C3); 124.6 (C1); 119.0 (C1 ); 114.7 (C8); 113.7 (C6); 111.0 (C10); 92.54
19
(1.12 g) 1H NMR (500 MHz, CD3CN):
d
7.31 (d, J ¼ 8.2 Hz, 4H, H2, H6,
0
0
(C4 ). F NMR (376 MHz, DMSO): ꢁ133.90 (s, 1F, F5 ); ꢁ145.20 (d,
0
0
0
0
H2 , H6 ); 6.62 (d, J ¼ 8.2 Hz, 4H, H3, H5, H3 , H5 ); 4.09 (brs, 4H,
0
0
J ¼ 28 Hz, 1F, F2 ); ꢁ157.93 (d, J ¼ 28 Hz, 1F, F3 ). Elemental analysis
found (calcd) (þNaþ; þ2 Clꢁ; þ2H3Oþ; þH2O): C 26.57 (26.57); H
2.20 (2.09); N 5.46 (5.81). HPLC (Gradient A) tR ¼ 12.30 min. MS
(ESI)ꢁ: m/z 569.9 [M ꢁ H]ꢁ. UV vis lmax ¼ 539 nm.
2 ꢃ NH2).
4.2.3.25. 3,30-Dimethyl-[1,10-biphenyl]-4,40-bis(diazonium),
6a.
Following the general procedure A, tolidine (637 mg, 3 mmol), HCl
37% (1 mL, 12 mmol), NaNO2 in solid (166 mg, 2.4 mmol), solvent
H2O/EtOH. The crude product was concentrated in vacuo then
extracted by adding 200 mL of HCL 1 M solution to pH ¼ 2 and
EtOAc. Compound was obtained as an orange powder in 41% yield
0
4.2.3.22. (E)-5-Ammonio-3-(2-(4-bromo-2-methoxyphenyl)hydra-
zono)-4-oxo-3,4-dihydronaphthalene-2,7-disulfonate, 4o (LSP9-
2122). Following the general procedure B, corresponding diazo-
nium salt (2.4 mmol) was added to 5-Amino-4-hydroxy-
naphthalene-2,7-disulfonic acid monosodium salt (716 mg,
2.1 mmol). Compound was obtained as a violet powder in 20% yield
(300 mg). 1H NMR (500 MHz, MeOD):
d
8.59 (d, J ¼ 8.8 Hz, 1H, H6 );
0
0
8.15 (d, J ¼ 1.2 Hz, 1H, H3 ); 8.07 (dd, J ¼ 8.8 Hz, J ¼ 1.2 Hz, 1H, H5 );
(245 mg). 1H NMR (500 MHz, DMSO):
d
15.35 (s, 1H, NH); 7.85 (d,
7.84 (d, J ¼ 1.8 Hz, 1H, H3 ); 7.79 (dd, J ¼ 8.2 Hz, J ¼ 1.8 Hz, 1H, H5 );
00
00
0
0
00
00
J ¼ 8.6 Hz, 1H, H6 ); 7.33 (d, J ¼ 1.7 Hz, 1H, H3 ); 7.29 (s, 1H, H1); 7.24
7.37 (d, J ¼ 8.2 Hz, 1H, H6 ); 2.85 (s, 3H, H7’); 2.45 (s, 3H, H7 ).