S. Hinsberger et al. / European Journal of Medicinal Chemistry 76 (2014) 343e351
349
NMR (500 MHz, CDCl3)
(m, 2H), 7.78e7.73 (m, 4H), 7.68e7.64 (m, 2H), 7.52e7.39 (m, 6H),
3.97 (s, 3H, OCH3) ppm. 13C NMR (125 MHz, CDCl3)
150.2, 145.7, 145.1, 139.9, 133.2, 132.3, 129.3, 129.1, 129.0, 128.2,
128.0, 127.6, 127.2, 126.2, 118.1, 109.1, 52.1 (OCH3) ppm. LC/MS: m/
z ¼ 414 [M þ Hþ], 827 [2M þ Hþ]; tR ¼ 17.93 min; 97.1% pure (UV).
6.2.2.2.6. Methyl 3-([1,10-biphenyl]-4-ylcarboxamido)-5-(4-
chlorophenyl)thiophene-2-carboxylate (47a). Beige solid, yield:
d
¼ 11.28 (s, 1H, NH), 8.60 (s, 1H), 8.15e8.09
d6)
d
¼ 10.49 (s, 1H, NH), 8.47 (s, 1H), 8.15e8.05 (m, 3H), 7.84 (d,
J ¼ 8.3 Hz, 2H), 7.76 (d, J ¼ 7.3 Hz, 2H), 7.72e7.65 (m, 1H), 7.56e7.47
d
¼ 165.2, 164.0,
(m, 3H), 7.47e7.36 (m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
d
¼ 167.2, 165.3, 143.3, 139.5, 139.1, 133.4, 131.3, 129.1, 128.9, 128.4,
128.2, 126.9, 126.6, 124.5, 121.2, 116.9 ppm. LC/MS: m/z ¼ 318
[M þ Hþ], 359 [M þ Hþ þ CH3CN]; tR ¼ 11.17 min; 99.0% pure (UV).
6.2.3.2. 3-([1,10-Biphenyl]-4-ylcarboxamido)-4-bromobenzoic
(40). White solid, yield: 89%. Mp: 281e282 ꢁC. 1H NMR (500 MHz,
DMSO-d6)
¼ 10.24 (s, 1H, NH), 8.15e8.12 (m, 2H), 8.12e8.09 (m,
1H), 7.90e7.85 (m, 3H), 7.80e7.74 (m, 3H), 7.55e7.49 (m, 2H), 7.46e
7.40 (m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
143.5, 139.1, 136.9, 133.2, 132.5, 130.8, 129.1, 129.0, 128.4, 128.2,
128.2, 127.0, 126.7, 125.5 ppm. LC/MS: m/z ¼ 396 and 398 [M þ Hþ],
437 and 439 [M þ Hþ þ CH3CN]; tR ¼ 12.60 min; 97.3% pure (UV).
acid
28%. 1H NMR (500 MHz, CDCl3)
d
¼ 11.26 (s, 1H, NH), 8.58 (s, 1H),
8.13e8.09 (m, J ¼ 8.2 Hz, 2H), 7.78e7.75 (m, J ¼ 8.5 Hz, 2H), 7.68e
d
7.62 (m, 4H), 7.52e7.48 (m, 2H), 7.46e7.38 (m, 3H), 3.97 (s, 3H,
OCH3) ppm. 13C NMR (125 MHz, CDCl3)
d
¼ 165.1, 164.0, 148.6, 145.7,
d
¼ 166.3, 165.1,
145.2, 139.8, 135.3, 132.1, 131.7, 129.3, 129.0, 128.2, 128.0, 127.6, 127.4,
127.2, 118.4, 109.3, 52.2 (OCH3) ppm. LC/MS: m/z ¼ 448 and 450
[M þ Hþ], 895 and 899 [2M þ Hþ]; tR ¼ 18.42 min; 99.1% pure (UV).
6.2.2.2.7. Ethyl 2-([1,10-biphenyl]-4-ylcarboxamido)-5-
phenylthiophene-3-carboxylate (49a). Yellow solid, yield: 40%. 1H
6.2.3.3. 3-([1,10-Biphenyl]-4-ylcarboxamido)-5-bromobenzoic
(41). Beige solid, yield: 94%. Mp: 285e286 ꢁC. 1H NMR (500 MHz,
DMSO-d6)
¼ 10.60 (s, 1H, NH), 8.46e8.37 (m, 2H), 8.12e8.06 (m,
2H), 7.89e7.84 (m, 2H), 7.81e7.73 (m, 3H), 7.54e7.48 (m, 2H), 7.48e
7.39 (m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
143.5, 141.0, 139.0, 133.2, 132.9, 129.1, 128.5, 128.2, 126.9, 126.7,
126.5, 126.2, 121.4, 119.9 ppm. LC/MS: m/z ¼ 396 and 398 [M þ Hþ],
437 and 439 [M þ Hþ þ CH3CN]; tR ¼ 13.01 min; 99.4% pure (UV).
acid
NMR (500 MHz, CDCl3)
d
¼ 12.10 (s, 1H, NH), 8.16e8.10 (m, 2H),
7.80e7.77 (m, 2H), 7.68e7.62 (m, 4H), 7.52e7.48 (m, 3H), 7.46e7.38
(m, 3H), 7.33e7.28 (m, 1H), 4.45 (q, J ¼ 7.3 Hz, 2H, OCH2), 1.47 (t,
d
J ¼ 7.3 Hz, 3H, CH3) ppm. 13C NMR (125 MHz, CDCl3)
d
¼ 166.0,
d
¼ 165.9, 165.5,
163.3, 148.6, 145.5, 139.7, 134.0, 133.8, 130.7, 129.0, 129.0, 128.3,
128.1, 127.6, 127.5, 127.3, 125.5, 119.3, 114.1, 61.0 (OCH2), 14.4 (CH3)
ppm. LC/MS: m/z ¼ 428 [M þ Hþ], 469 [M þ Hþ þ CH3CN], 855
[2M þ Hþ]; tR ¼ 18.34 min; >99.9% pure (UV).
6.2.3.4. 4-([1,10-Biphenyl]-4-ylcarboxamido)benzoic acid (42) [12].
6.2.2.3. General procedure for the synthesis of 36 and 48a. The appro-
priate alkyl aminobenzoate or alkyl aminothiophenecarboxylate
(1 equiv) and the acyl chloride (1.2 equiv) were dissolved in toluene
and refluxed for 4 h (36) or 18 h (48a). For purification the solvent
was removed under reduced pressure and the remaining solid sus-
pended in MeOH. After filtration the precipitate was washed with
MeOH to yield the pure compound.
Beige solid, yield: 92%. Mp: 337 ꢁC (decomposition). 1H NMR
(500 MHz, DMSO-d6)
d
¼ 10.58 (s, 1H, NH), 8.08 (d, J ¼ 8.3 Hz, 2H),
7.99e7.91 (m, 4H), 7.85 (d, J ¼ 8.3 Hz, 2H), 7.80e7.74 (m, 2H), 7.54e
7.48 (m, 2H), 7.46e7.40 (m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
d
¼ 167.0, 165.6, 143.4, 143.3, 139.1, 133.4, 130.3, 129.1, 128.5, 128.2,
127.0, 126.6, 125.5, 119.5 ppm. LC/MS: m/z ¼ 318 [M þ Hþ], 359
[M þ Hþ þ CH3CN]; tR ¼ 11.29 min; 99.4% pure (UV).
6.2.2.3.1. N-(4-Bromo-2-carbamoylphenyl)-[1,10-biphenyl]-4-
carboxamide (36). White solid, yield: 79%. Mp: 254e256 ꢁC. 1H
6.2.3.5. 3-([1,10-Biphenyl]-4-ylcarboxamido)thiophene-2-carboxylic
NMR (500 MHz, DMSO-d6)
d
¼ 12.93 (s, 1H, NH), 8.68 (d, J ¼ 9.1 Hz,
acid (43) [13]. Yellow solid, yield: 87%. Mp: 242e243 ꢁC. 1H NMR
1H), 8.54 (br. s., 1H), 8.11 (d, J ¼ 2.5 Hz, 1H), 8.04e7.97 (m, 3H),
(500 MHz, DMSO-d6)
d
¼ 11.27 (s, 1H, NH), 8.13 (d, J ¼ 5.5 Hz, 1H),
7.90e7.86 (m, 2H), 7.79e7.74 (m, 3H), 7.54e7.48 (m, 2H), 7.46e7.41
8.01 (d, J ¼ 8.5 Hz, 2H), 7.95e7.87 (m, 3H), 7.80e7.73 (m, 2H), 7.54e
(m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
d
¼ 169.8, 164.2, 143.7,
7.48 (m, 2H), 7.47e7.39 (m, 1H) ppm. 13C NMR (125 MHz, DMSO-d6)
139.4, 138.9, 135.2, 133.1, 131.2, 129.1, 128.3, 127.7, 127.2, 127.0, 122.1,
121.1, 114.4 ppm. LC/MS: m/z ¼ 395 and 397 [M þ Hþ], 789 and 791
[2M þ Hþ]; tR ¼ 14.07 min; >99.9% pure (UV).
d
¼ 165.5, 163.0, 144.0, 143.8, 138.8, 132.6, 132.1, 129.1, 128.4, 127.8,
127.3, 127.0, 121.8, 112.0 ppm. LC/MS: m/z ¼ 324 [M þ Hþ], 365
[M þ Hþ þ CH3CN], 647 [2M þ Hþ]; tR ¼ 12.80 min; 99.8% pure (UV).
6.2.2.3.2. Methyl 3-([1,10-biphenyl]-4-ylcarboxamido)-5-(4-
methoxyphenyl)thiophene-2-carboxylate (48a). Yellow solid, yield:
6.2.3.6. 4-([1,10-Biphenyl]-4-ylcarboxamido)thiophene-3-carboxylic
82%. 1H NMR (500 MHz, CDCl3)
d
¼ 11.29 (s, 1H, NH), 8.49 (s, 1H),
acid (44) [13]. Yellow solid, yield: 90%. Mp: 265e265 ꢁC. 1H NMR
8.15e8.09 (m, 2H), 7.78e7.74 (m, 2H), 7.70e7.63 (m, 4H), 7.54e7.47
(m, 2H), 7.46e7.39 (m, 1H), 7.00e6.92 (m, 2H), 3.96 (s, 3H, OCH3),
(500 MHz, DMSO-d6)
d
¼ 11.23 (s, 1H, NH), 8.39 (d, J ¼ 3.5 Hz, 1H),
8.10 (d, J ¼ 3.5 Hz, 1H), 8.01e7.97 (m, 2H), 7.93e7.87 (m, 2H), 7.79e
3.87 (s, 3H, OCH3) ppm. 13C NMR (125 MHz, CDCl3)
d
¼ 165.3, 164.0,
7.73 (m, 2H), 7.55e7.48 (m, 2H), 7.46e7.41 (m, 1H) ppm. 13C NMR
160.6, 150.4, 145.8, 145.1, 139.9, 132.3, 129.0, 128.1, 128.0, 127.6,
127.5, 127.2, 125.9, 117.0, 114.5, 108.0, 55.4 (OCH3), 52.0 (OCH3) ppm.
LC/MS: m/z ¼ 444 [M þ Hþ], 485 [M þ Hþ þ CH3CN], 887
[2M þ Hþ]; tR ¼ 17.96 min; 97.3% pure (UV).
(125 MHz, DMSO-d6)
132.4, 129.1, 128.3, 127.4, 127.3, 126.9, 122.7, 110.6 ppm. LC/MS: m/
z ¼ 324 [M þ Hþ], 647 [2M þ Hþ]; tR ¼ 12.82 min; 99.5% pure (UV).
d
¼ 165.7, 163.2, 143.7, 138.9, 136.0, 133.9,
6.2.3.7. 2-([1,10-Biphenyl]-4-ylcarboxamido)thiophene-3-carboxylic
6.2.3. General procedure for the synthesis of benzamidobenzoate or
benzamidothiophenecarboxylate derivatives 39e47,50 (estercleavage)
The methyl or ethyl esters of the title compounds (39ae47a,
50a) were hydrolyzed with 5 M NaOH in THF/MeOH (2:1) at room
temperature (18 h). The mixture was acidified by the addition of
1 M HCl, filtered and the precipitate was washed with 1 M HCl to
provide the title compounds (39, 50). If the compound was not pure
at this stage of procedure it was washed with CH2Cl2 (41e43) or
CH2Cl2 and MeOH (40, 44e47).
acid (45). Brown solid, yield: 92%. Mp: 242e244 ꢁC. 1H NMR
(500 MHz, DMSO-d6)
d
¼ 12.12 (s, 1H, NH), 8.03e8.00 (m, 2H),
7.95e7.91 (m, 2H), 7.79e7.75 (m, 2H), 7.54e7.50 (m, 2H), 7.48e7.41
(m,1H), 7.24 (d, J ¼ 5.7 Hz,1H), 7.08 (d, J ¼ 5.7 Hz,1H) ppm. 13C NMR
(125 MHz, DMSO-d6)
d
¼ 166.8, 162.5, 147.9, 144.3, 138.7, 130.6,
129.1, 128.4, 127.8, 127.4, 127.0, 124.3, 116.9, 114.1 ppm. LC/MS: m/
z ¼ 324 [M þ Hþ], 365 [M þ Hþ þ CH3CN], 647 [2M þ Hþ];
tR ¼ 13.53 min; 96.2% pure (UV).
6.2.3.8. 3-([1,10-Biphenyl]-4-ylcarboxamido)-5-phenylthiophene-2-
6.2.3.1. 3-([1,10-Biphenyl]-4-ylcarboxamido)benzoic
White solid, yield: 42%. Mp: 288e289 ꢁC. 1H NMR (500 MHz, DMSO-
acid
(39).
carboxylic acid (46). Beige solid, yield: 81%. Mp: 224e225 ꢁC. 1H
NMR (500 MHz, DMSO-d6)
d
¼ 11.31 (s, 1H, NH), 8.46 (s, 1H), 8.05e