A mild and efficient method of synthesis of a series of new multi-dentate ligands

Article abstract of DOI:10.1081/SCC-120022169

A series of esters and amides of diethylenetriamine-penta-acetic acid have been synthesized from diethylene triamine penta acetic acid (DTPA) with an efficient and mild synthesis method. All these compounds obtained were characterized by Fab-MS, ¹H ¹HNMR, IR, and elemental analysis.

Full text of DOI:10.1081/SCC-120022169

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2811–2815, 2003
A Mild and Efficient Method of Synthesis
of a Series of New Multi-dentate Ligands
1
2
Hui An Tang,1,2, Sheng Yang, and Ru Dong Yang
*
1Chemistry Department of TianShui Normal
University, TianShui, Gansu Province, P.R. China
2College of Chemistry and Chemical Engineering of
LanZhou University, P.R. China
ABSTRACT
A series of esters and amides of diethylenetriamine-penta-acetic acid
have been synthesized from diethylene triamine penta acetic acid
(DTPA) with an efficient and mild synthesis method. All these
compoundsobtained were characterized by Fab-MS, 1H NMR, IR,
and elemental analysis.
Key Words: Esters and amides of diethylenetriamine-penta-acetic
acid; Efficient and mild synthesis method.
*Correspondence: Hui An Tang, College of Chemistry and Chemical
Engineering of LanZhou University, 730000, P.R. China; Chemistry Department
of TianShui Normal University, TianShui, 741018, Gansu, P.R. China; E-mail:
huiantang@sina.com.cn.
2811
DOI: 10.1081/SCC-120022169
Copyright & 2003 by Marcel Dekker, Inc.
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2812
Tang, Yang, and Yang
Several typesof the ligand of paramagnetic metal ion–chelate
complexes have been proposed for use as contrast-enhancing agents in
magnetic resonance imaging (MRI). Gd (DTPA)2ꢀ is the first of these
agents to be approved for use in humans. It has good stability, solubility,
highly relaxation, low toxicity, and fast metabolism but unfortunately
high osmotic pressure due to multi-charge complexes. Only Zuo[1] has
synthesized a few of such non-ion complexes with derivatives of diethy-
lene triamine pentaacetic acid with low osmotic pressure. We designed
and synthesize a series of esters and imides of diethylene triamine penta
acetic acid from DTPA (Diethylene triamine penta-acetic acid).
Afterwards, many complexes of Rare earths [Gd(III)] with them were
synthesized (reported in another article). We suggest that non-ion com-
plexeswill be formed from thees ligandsand [Gd(III)] according to
charge law. They may be a new type of potential MRI and with low
osmotic pressure due to non-ion complexes. Otherwise, these ligands
(a, b, c, d, e) are poly-dentate, and may be used as multi-dentate ligand
to bind metal ionsasdetoxification of heavy metal ions. In thisarticle we
report the synthesis of these ligands. The synthesis method is a quite mild
and convenient. The synthetic route is showed in Sch. 1.
EXPERIMENTAL
All melting pointswere uncorrected. All yieldsrefer to isolated prod-
ucts. Infrared spectra were recorded on a Nicolet-5DX spectrometer
1
(KBr). H NMR spectra were obtained on a JEOL-FX90Q instrument
in DMSO with Me4Si asinternal tsandard. Elementary analyesswere
performed at ErlO-1106 instrument.
General Preparation Route
DTPAA (diethylene triamine penta acetic acid bi-anhydride)
[2]
hasbeen prepared referring to Lit.
a, b, c, d, e were synthesized as
following: (1) diester: for instance, a: 2 mmol 2,2-bis(hydroxyl-methyl)-
1,3-propanediol was dissolved in 50 mL distilled water, put 1 mmol
DTPAA and 5 mL Py into the aqueous solution, stir for 36 h at the
room temperature. Then continuously stir about 6 h at about 60ꢁC, dis-
tille out Py, H2O, and cool it down to the room temperature. The residues
dissolve into H2O and drop 5 mL EtOH and 8 mL Et2O white power
produce. Filter and wash it with a little cool EtOH three times. Finally,
dry it in vacuum with P4O10. Recrystallized from H2O–Et2O–EtOH asthe

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Paramagnetic Metal Ion-Chelate Complexes
2813
CH2OH
O
O
O
CH2OH
C
CH2O
HO
HOCH2
OH
N
N
N
(a)
OCH2
C
CH2OH
HOCH2
O
O
CH2OH
S
OH
NH2
NH
HN
CH2OH
O
CH2OH
O
HO
C
CH2OH
2 HOCH2
Py
HO
HO
S
O
HO
OH
HN
N
N
N
NH
CH2OH
NH
C
NH2
NH2
O
OH
O
O
O
O
OH
N
(b)
2
H2N
S
C
HOH2C
HO
O
NH
Py
O
OH
N
(c)
O
2
HO
HO
NH2
N
O
O
O
O
O
O
HO
HO
OH
OH
N
N
O
N
N
O
N
N
HO
OH
O
OH
OH
OH
CH2OH
O
O
O
O
OH
O
OH
HO
OH
OH
2
H2N
O
CH3
CH3
Py
C
N
HO
Py
2
N
OH
N
O
OH
OH
O
HO
O
OH
HO
HO
N
H3C
H3C
N
N
O
OH
OH
O
N
O
O
O
OH
OH
O
C
O
OH
N
N
OH
NH
N
O
NH
OH
O
HO
O
CH3
C
N
(e)
OH
OH
(d)
O
N
CH3
Scheme 1. The synthesis route of ligands (biimides and biesters).
final products e: prepared as above method. (2) b: di-imides. First,
2 mmol thiosemicarbazide is dissolved in 50 mL distilled water, put
1 mmol DTPAA and 15 mL Py into the aqueous solution, stir for 36 h
at the room temperature. Second, continuously stir about 24 h at about
60ꢁC, distill out Py, H2O in reduced pressure, and then cool it down to
the room temperature. The residues dissolve into H2O, and drop 5 mL
EtOH and 8 mL Et2O white power produce. Filter and wash it with a
little cool EtOH three times. Finally, dry it in vacuum with P4O10.
Recrystallized from H2O–Et2O–EtOH asthe final productsd and c are
prepared asb.

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2814
Tang, Yang, and Yang
Table 1. The elemental analysis of ligands found (cal.)%.
Empirical formula Mw Yield (%)
C
H
N
H3L (a)
C24H43N3O16
629.2
87
85
89
86
85
45.91
6.47
6.80
(45.81) (6.85) (6.67)
32.71 6.00 21.34
(32.90) (5.81) (21.37)
35.49 7.79 7.26
(35.23) (7.90) (7.26)
53.92 6.57 15.48
(54.22) (6.22) (15.80)
43.18 5.63 5.68
(43.50) (6.00) (6.00)
H3L2ꢂ5H2O (b) C16H34N9O10.5S2 584.5
H3L9ꢂ5H2O (c) C26H64N5O27.5
886.3
799.4
717.3
H3Lꢂ2H2O (d)
C36H49N9O12
H3L (e)
C26H43N3O20
All these ligands are easily soluble in water, DMSO and DMF.
Slightly soluble in methanol but insoluble in acetone, chloroform, and
1
Et2O. Their structure were characterized by IR, Fab-MS, H NMRnote
Elemental analysisand yield isshown in Table 1. The elemental analysis
.
are in good agreement with a–e. Respectively, the MS spectra reveal that
the molecular ion peaksare in accordance with the given structure of a–e.
1H NMR, IR are comformed with the structures.
Notes
(a) Yield: 87%. IR (cmꢀ1): 3431, 3073, 3023, 2541, 2361, 1729, 1699,
1
1634, 1531, 1410, 1348, 1297, 1245, 1205, 1145. H NMR (DMSO-d6):
ꢀ2.60 (s, 16H, -CH2OH), ꢀ3.10 (t, 8H, -NCH2CH2N-), ꢀ3.53 (s, 10H,
-CO-CH2-N). FAB-Ms: m/z ¼ 629.
(b) Yield: 85%. IR (cmꢀ1): 3324, 3230, 1713, 1654, 1620, 1315.
1H NMR (DMSO-d6): ꢀ2.86 (t, 8H, –NCH2CH2N-), ꢀ3.52 (s, 10H,
–CO-CH2-N). FAB-Ms: m/z ¼ 539.
(c) Yield: 89%. IR (cmꢀ1): 3349, 3291, 3098, 3032, 1728, 1696, 1634,
1617, 1584, 1420, 1384, 1353, 1337, 1316, 1248, 1182, 1139, 1093, 1034,
1002, 912, 888, 854, 773, 598. 1H NMR (DMSO-d6): ꢀ2.95 (d, 4H,
-CH2OH), ꢀ3.49 (t, 8H, -NCH2CH2N-), ꢀ3.60 (m, 8H, sugar ring),
ꢀ4.95 (t, 12H, ring-CH-NH). FAB-Ms: m/z ¼ 715.
(d) Yield: 86%. IR (cmꢀ1): 3426, 3259, 3012, 1701, 1646, 1593, 1492,
1456, 1412, 1310, 1218. 1H NMR (DMSO-d6): ꢀ2.10 (s, 6H, C-CH3),
ꢀ3.10 (m, 14H, N-CH3; -NCH2 CH2N-), ꢀ3.49 (s, 10H, CO-CH2-N), ꢀ
6.9–7.9 (m, 10H, Ar-H). FAB-Ms: m/z ¼ 763.

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Paramagnetic Metal Ion-Chelate Complexes
2815
1
(e) Yield: 85%. IR (cmꢀ1): 3346, 3281, 1713, 1654, 1389. H NMR
(DMSO-d6): ꢀ3.36 (t, 8H, -NCH2CH2N-), ꢀ3.36 (s, 10H, -CO-CH2-N,),
ꢀ3.90 (d, 10H, ring-H), ꢀ5.95 (d, 2H, bridge end). FAB-Ms: m/z ¼ 717.
REFERENCES
1. Zuo Renxi. Paramagnetic metal chelatesof DTPA dipyridoxoletser
derivativesand their NMRT relaxivitiesin water. Sci. Bulletin 1997,
42 (14), 1519–1524.
2. Geigy, J.R. Fr. Patent 1,548,888.
Received in Japan November 20, 2002

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