Synthesis of Novel Succinic Acid Derivatives
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
157
extensive biological activity have been successfully
conjugated with tartaric acid and malic acid. We expect these
new compounds have better biological activity.
1578, 1528, 1254, 1123, 1072, 1026, 845; ESI-MS m/z:
[M+Na]+ 321.12; 1H NMR (DMSO-d6, 600 MHz): ꢀ 3.82 (s,
3H), 4.39 (s, 2H), 5.05 (s, 1H), 5.74 (s, 1H), 7.01 (d, J = 9.0
Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 9.67 (s, 1H), 10.30 (s,
1H), 12.66 (s, 1H).
EXPERIMENTAL
All reagents were obtained from commercial suppliers
and used without further purification except SOCl2,
methanol and triethylamine. All the solvents were purified
before use. All reactions were monitored by thin-layer
chromatography on 0.25 mm silica gel plates (GF-254).
Melting points were determined on an electrothermal
melting point apparatus and were uncorrected. ESI mass
spectra were recorded using a Waters ZQ4000/2695 LC–MS
spectrometer. Infrared spectra were obtained as KBr pellets
Synthesis of 2,3-dihydroxy-N-(5-phenyl- [1,3,4]thiadiazol-
2-yl)-succinamic acid (5a)
To the solution of 2-amino-5-phenyl-1,3,4- thiadiazole
(3.54 g, 0.020 mol) in THF and excess triethylamine
dropwise added the solution of compound (3) (6.40 g, 0.024
mol) in THF which was derived from diacetyl-tartaric
anhydride reacted with anhydrous methanol and then SOCl2.
The solvent was removed with a rotary evaporator after 24
hours and the residue was hydrolyzed in a solution of K2CO3
in methanol at 65°C for 12 hours to afford compound (5a)
(5.31 g, 86%); Mp 210°C (decomposition); IR (KBr, cmꢁ1):
3242, 1736, 1693, 1533, 1466, 1304, 1269, 1146, 1082, 762,
683; ESI-MS m/z: [M+H]+ 310.08; 1H NMR (DMSO-d6, 600
MHz): ꢀ 4.47 (d, J = 1.8 Hz, 1H), 4.63 (s, 1H), 5.37 (s, 1H),
5.89 (s, 1H), 7.53-7.55 (m, 3H), 7.95-7.96 (q, 2H), 12.18 (s,
1H), 12.78 (s, 1H).
1
on a Shimadzu FTIR-8000 spectrometer. H NMR spectra
were obtained in DMSO on a Bruker 600 MHz spectrometer.
The chemical shifts were reported in ꢀ values (ppm) relative
to tetramethylsilane (TMS) as internal standard.
Synthesis of (2R, 3R)-2,3-dihydroxy-4-(N'-Benzoyl-hydr-
azino)-4-oxo-butyric acid (4a)
The product (4a) was prepared from the reaction of
diacetyl-l-tartaric anhydride with benzoic acid hydrazide in
THF for 30 minutes. Finally, acetyls were removed by 1 M
NaOH. Purification was by recrystallization from chloroform
if necessary. White solid (yield 92%); Mp 128-130°C; IR
(KBr, cmꢁ1): 3533, 3476, 3360, 3213, 3028, 1744, 1693,
1651,1578, 1528, 1273, 1123, 1072, 694; ESI-MS m/z:
[M+Na]+ 291.10; 1H NMR (DMSO-d6, 600 MHz): ꢀ 4.39 (s,
2H), 5.04 (s, 1H), 5.76 (d, J = 6.0 Hz, 1H), 7.47-7.50 (q,
2H), 7.55-7.58 (m, 1H), 7.89-7.90 (q, 2H), 9.74 (d, J = 1.2
Hz, 1H), 10.44 (d, J = 1.2 Hz, 1H), 12.68 (s, 1H).
2,3-dihydroxy-N-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-succ-
inamic acid (5b)
White solid (4.39 g, 68%); Mp 162-163°C; IR (KBr,
cmꢁ1): 3256, 1736, 1693, 1533, 1308, 1269, 1150, 1082, 700,
669; ESI-MS m/z: [M+H]+ 324.02; 1H NMR (DMSO-d6, 600
MHz): ꢀ 4.36 (s, 2H), 4.40 (d, J = 1.8 Hz, 1H), 4.55 (s, 1H),
5.30 (s, 1H), 5.83 (s, 1H), 7.26-7.29 (m, 1H), 7.32-7.36 (m,
4H), 11.89 (s, 1H), 12.74 (s, 1H).
2,3-dihydroxy-N-[5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-
2-yl]-succinamic acid (5c)
(2R, 3R)-2,3-dihydroxy-4-(N'-phenylacetyl- hydrazino)-4-
oxo-butyric acid (4b)
White solid (6.03 g, 89%); Mp 193-194°C; IR (KBr,
cmꢁ1): 3240, 1740, 1693, 1609, 1535, 1462, 1308, 1258,
White solid (yield 81%); Mp 120-122°C; IR (KBr, cmꢁ1):
3530, 3476, 3387, 3206, 3028, 1740, 1697, 1659, 1570,
1520, 1420, 1238, 1111, 1072, 721, 694; ESI-MS m/z:
[M+Na]+ 305.13; 1H NMR (DMSO-d6, 600 MHz): ꢀ 3.48 (s,
2H), 4.33 (s, 2H), 5.02 (s, 1H), 5.71 (s, 1H), 7.23 (t, J = 3.0
Hz, 1H), 7.28-7.30 (q, 4H), 9.62 (d, J = 2.4 Hz, 1H), 10.25
(d, J = 2.4 Hz, 1H), 12.64 (s, 1H).
1
1142, 1084, 1034, 833; ESI-MS m/z: [M+H]+ 340.07; H
NMR (DMSO-d6, 600 MHz): ꢀ 3.83 (s, 3H), 4.47 (s, 1H),
4.61 (d, J = 3.6 Hz, 1H), 5.36 (s, 1H), 5.88 (d, J= 6.0 Hz,
1H), 7.09 (dd, J= 1.8 Hz, 7.2 Hz, 2H), 7.89 (dd, J = 1.8 Hz,
6.6 Hz, 2H), 12.07(s, 1H), 12.78 (s, 1H).
2,3-dihydroxy-N-[5-(1-Ethyl-pentyl)-[1,3,4]thiadiazol-2-
yl]-succinamic acid (5d)
(2R, 3R)-2,3-dihydroxy-4-[N'-(4-Fluoro-benzoyl)-hydra-
zino]-4-oxo-butyric acid (4c)
White solid (4.30 g, 65%); Mp 130-132°C; IR (KBr,
cmꢁ1): 3233, 2959, 2932, 2858, 1697, 1535, 1458, 1312,
1142, 1080; ESI-MS m/z: [M+H]+ 332.09; 1H NMR
(DMSO-d6, 600 MHz): ꢀ 0.80-0.84 (m, 6H), 1.20-1.30 (m,
4H), 1.61-1.65 (m, 2H), 1.70-1.75 (m, 2H), 2.99-3.04 (m,
1H), 4.43 (d, J = 2.4 Hz, 1H), 4.57 (d, J = 2.4 Hz, 1H), 5.34
(s, 1H), 5.84 (s, 1H), 11.86 (s, 1H), 12.76 (s, 1H).
White solid (yield 84%); Mp 165-166°C; IR (KBr, cmꢁ1):
3533, 3479, 3340, 3209, 3017, 1740, 1693, 1651, 1605,
1508, 1273, 1246, 1123, 1072, 853; ESI-MS m/z: [M+Na]+
309.10; 1H NMR (DMSO-d6, 600 MHz): ꢀ 4.39 (s, 2H), 5.04
(s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 7.33 (t, J = 9.0 Hz, 2H),
7.97 (dd, J = 5.4 Hz, 9.0 Hz, 2H), 9.75 (d, J = 1.8 Hz, 1H),
10.48 (d, J = 1.8 Hz, 1H), 12.69 (s, 1H).
Synthesis of 3-hydroxy-4-oxo-4-(5-phenyl-1,3,4-thiadia-
zol-2-ylamino)butanoic acid (6a)
(2R, 3R)-2,3-dihydroxy-4-[N'-(4-methoxy-benzoyl)-hydr-
azino]-4-oxo-butyric acid (4d)
White solid (yield 87%); Mp 121-122°C; IR (KBr, cmꢁ1):
3533, 3479, 3340, 3206, 3016, 1740, 1690, 1647, 1608,
The product was prepared from the reaction of compound
(1) (3.79 g, 0.024 mol) with 2-amino-5-phenyl-1,3,4-
thiadiazole (3.54 g, 0.020 mol) in THF at 0°C for 48 hours.