B. Sun et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
9
4.2. General procedure for the synthesis of
L
-serine ester (11a–e
)
129.50 (2ꢁArCH), 128.60 (ArCH), 128.47 (2ꢁArCH), 127.81
(ArCH), 127.37 (2ꢁArCH), 127.10 (2ꢁArCH), 120.41 (ArCH), 66.88
(CH2), 54.25 (CH), 46.25 (CH2), 21.92 (CH2), 10.66 (CH3). ESI-MS
m/z: 378.2 [M+H]+; 400.3 [M+Na]+; 376.2 [MꢀH]ꢀ.
Thionylchloride (1 equiv) was added dropwise to the alcohol at
a rate to maintain the temperature below 5 °C. After 30 min,
L-serine 9a–9l (3 equiv) was added in the reaction under reflux
for 24–48 h, respectively. Then the alcohol was removed under
reduced pressure, final white solid was obtained.
4.4.4. Isopropyl 2-([1,10-biphenyl]-4-ylcarboxamido)-3-(1H-
imidazol-1-yl)propanoate (18)
Light white solid; yield: 55.9%; mp: 144.9–149.7 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): d 9.02 (d, J = 7.9 Hz, 1H), 7.90 (d,
J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.3 Hz, 2H),
7.65 (s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.24 (s,
1H), 6.87 (s, 1H), 4.96 (m, J = 18.7 Hz, 1H), 4.85–4.71 (m, 1H),
4.47 (d, J = 35.3 Hz, 2H), 1.20 (t, J = 5.9 Hz, 6H). 13C NMR
(150 MHz, DMSO-d6) d(ppm): 170.12 (C@O), 166.70 (C@O),
143.70 (ArC), 139.54 (ArC), 138.30 (ArCH), 132.66 (ArC), 129.51
(2ꢁArCH), 128.76 (ArCH), 128.61 (ArCH), 128.49 (2ꢁArCH),
127.38 (2ꢁArCH), 127.10 (2ꢁArCH), 120.37 (ArCH), 61.53 (CH),
54.24 (CH), 46.25 (CH2), 21.92 (CH2), 14.48 (2ꢁCH3). ESI-MS m/z:
378.2 [M+H]+; 400.3 [M+Na]+; 376.2 [MꢀH]ꢀ.
4.3. General procedure for the synthesis of compounds
(12a–e, 13a–e, 14a–e
)
EDCI (1.1 equiv) and HOBt (1.1 equiv) were added to a solution
of appropriate organic acids 2, 6 and 10 (1 equiv) in anhydrous
DMF, respectively. The mixture was stirred at room temperature
for 2 h, then L-serine ester 11a–e (1.1 equiv) and DIEA (4 equiv)
were added, and the mixture was heated at 75 °C for 7 h. The reac-
tion mixture was poured into ice water, filtered and produced a
white solid.
4.4. General procedure for the synthesis of compounds (15–29)
4.4.5. Isobutyl 2-([1,10-biphenyl]-4-ylcarboxamido)-3-(1H-
imidazol-1-yl)propanoate (19)
To solution of compounds 12a–e, 13a–e, 14a–e (1 equiv) in
anhydrous CH3CN was added imidazole (2 equiv) and CDI (3 equiv).
The mixture was then heated under reflux for 7 h. The reaction mix-
ture was allowed to cool and then extracted with EtOAc and H2O.
The organic layer was dried (MgSO4) filtered and reduced in vacuo.
The product was purified by flash column chromatography.
Light white solid; yield: 55.9%; mp: 147.3–153.5 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 9.04 (d, J = 8.0 Hz, 1H), 7.89 (d,
J = 8.4 Hz, 2H), 7.82–7.70 (m, 4H), 7.46 (m, 7.3 Hz, 3H), 7.23 (s,
1H), 6.86 (s, 1H), 4.84 (m, 1H), 4.50 (d, J = 45.4 Hz, 2H), 3.91 (d,
J = 6.1 Hz, 2H), 1.87 (m, 1H), 0.87 (d, J = 6.7 Hz, 7H). 13C NMR
(150 MHz, DMSO-d6) d(ppm): 170.09 (C@O), 166.77 (C@O),
143.67 (ArC), 139.53 (ArC), 138.28 (ArCH), 132.71(ArC), 129.51
(2ꢁArCH), 128.78 (ArCH), 128.61 (ArCH), 128.44 (2ꢁArCH),
127.37 (2ꢁArCH), 127.10 (2ꢁArCH), 120.33 (ArCH), 71.11 (CH2),
54.27 (CH), 46.15 (CH2), 27.70 (CH), 19.21 (2ꢁCH3). ESI-MS m/z:
392.2 [M+H]+; 414.3 [M+Na]+; 390.2 [MꢀH]ꢀ.
4.4.1. Methyl 2-([1,10-biphenyl]-4-ylcarboxamido)-3-(1H-
imidazol-1-yl)propanoate (15)
Light white solid; yield: 53.2%; mp: 131.9–135.5 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 9.10 (d, J = 8.0 Hz, 1H), 7.93 (d,
J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.4 Hz, 2H),
7.70 (s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.3 Hz, 1H), 7.24
(s, 1H), 6.89 (s, 1H), 4.96–4.83 (m, 1H), 4.51 (d, J = 24.0 Hz, 2H),
3.71 (s, 3H). 13C NMR (150 MHz, DMSO-d6) d(ppm): 170.62(C@O),
166.69 (C@O), 143.74 (ArC), 139.54 (ArC), 138.30 (ArCH), 132.59
(ArC), 129.70 (ArCH), 129.50 (2ꢁArCH), 128.61 (ArCH), 128.52
(2ꢁArCH), 127.38 (2ꢁArCH), 127.10 (2ꢁArCH), 120.41 (ArCH),
54.14 (CH3), 52.78 (CH), 46.28 (CH2). ESI-MS m/z: 350.0 [M+H]+;
372.1 [M+Na]+; 348.1 [MꢀH]ꢀ.
4.4.6. Methyl 2-(5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carboxamido)-3-(1H-imidazol-1-yl)propanoate (20)
Light white solid; yield: 59.5%; mp: 141.3–145.8 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 8.46–8.44 (d, J = 8.0 Hz, 1H), 7.62
(s, 1H), 7.60–7.52 (m, 5H), 7.21 (s, 1H), 6.88 (s, 1H), 4.88–4.82
(m, 1H), 4.53–4.34 (d, J = 76 Hz, 2H), 3.33 (s, 3H), 2.22 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) d(ppm): 170.30 (C@O), 162.15 (C@O),
149.27 (ArC), 138.33 (ArCH), 137.61(ArC), 129.81 (2ꢁArCH),
129.43 (ArC), 128.83 (ArCH), 126.94 (ArCH), 125.81 (2ꢁArCH),
120.28 (ArCH), 114.66 (ArC), 71.11 (CH3), 52.81 (CH), 46.25
(CH2), 13.62 (CH3). ESI-MS m/z: 388.1 [M+H]+; 410.3 [M+Na]+;
386.2 [MꢀH]ꢀ.
4.4.2. Ethyl 2-([1,10-biphenyl]-4-ylcarboxamido)-3-(1H-
imidazol-1-yl)propanoate (16)
Light white solid; yield: 61.4%; mp: 137.4–141.1 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 9.04 (d, J = 7.9 Hz, 1H), 7.91 (d,
J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.4 Hz, 2H), 7.67
(s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.24 (s, 1H),
6.87 (s, 1H), 4.84 (m, 1H), 4.48 (d, J = 23.9 Hz, 2H), 4.16 (q, J = 7.1 Hz,
2H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) d(ppm):
169.64 (C@O), 166.74 (C@O), 143.67 (ArC), 139.56 (ArC), 138.31
(ArCH), 132.75 (ArC), 129.50 (2ꢁArCH), 128.82 (ArCH), 128.59
(ArCH), 128.47 (2ꢁArCH), 127.37 (2ꢁArCH), 127.10 (2ꢁArCH),
120.35 (ArCH), 69.11 (CH2), 54.38 (CH), 46.23 (CH2), 21.95 (CH3).
ESI-MS m/z: 364.2 [M+H]+; 386.3 [M+Na]+; 362.2 [MꢀH]ꢀ.
4.4.7. Ethyl 2-(5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carboxamido)-3-(1H-imidazol-1-yl)propanoate (21)
Light white solid; yield: 53.2%; mp: 144.9–148.5 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 8.48–8.46 (d, J = 8 Hz,1H), 7.66 (s,
1H), 7.58–7.52 (m, 5H), 7.23 (s, 1H), 6.90 (s, 1H), 4.84–4.79 (m,
1H), 4.53–4.35 (d, J = 72 Hz, 2H), 4.17 (q, J = 8 Hz, 2H), 2.23 (s,
3H), 1.22 (t, J = 8 Hz,3H). 13C NMR (150 MHz, DMSO-d6) d(ppm):
169.79 (C@O), 162.10 (C@O), 149.19 (ArC), 138.30 (ArCH), 137.64
(ArC), 129.80 (2ꢁArCH), 129.40 (ArC), 128.66 (ArCH), 126.87
(ArCH), 125.79 (2ꢁArCH), 120.34 (ArCH), 114.83 (ArC), 61.58
(CH2), 53.83 (CH), 46.28 (CH2), 14.45 (CH3), 13.59 (CH3). ESI-MS
m/z: 402.1 [M+H]+; 424.3 [M+Na]+; 400.2 [MꢀH]ꢀ.
4.4.3. Propyl 2-([1,10-biphenyl]-4-ylcarboxamido)-3-(1H-imida-
zol-1-yl)propanoate (17)
Light white solid; yield: 57.1%; mp: 142.1–146.2 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 9.04 (d, J = 8.0 Hz, 1H), 7.90 (d,
J = 8.4 Hz, 2H), 7.81–7.77 (m, 2H), 7.75–7.71 (m, 2H), 7.70 (s, 1H),
7.50 (t, J = 7.5 Hz, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 6.89
(s, 1H), 4.85 (m, 1H), 4.57–4.38 (d, J = 48 Hz, 2H), 4.07 (t,
J = 8.7 Hz, 2H), 1.59 (m, J = 20.8 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).
13C NMR (150 MHz, DMSO-d6) d(ppm): 170.15 (C@O), 166.74
(C@O), 143.69 (ArC), 139.54 (ArC), 138.24 (ArCH), 132.68 (ArC),
4.4.8. Propyl 2-(5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carboxamido)-3-(1H-imidazol-1-yl)propanoate (22)
Light white solid; yield: 63.7%; mp: 146.3–151.4 °C. 1H NMR
(400 MHz, DMSO-d6) d(ppm): 8.49–8.47 (d, J = 8.0 Hz, 1H), 7.69
(s, 1H), 7.60–7.53 (m, 5H), 7.25 (s, 1H), 6.92 (s, 1H), 4.86–4.81
(m, 1H), 4.54–4.36 (d, J = 72 Hz, 2H), 4.10–4.06 (t, J = 8 Hz, 2H),