R. Viguier, G. Serratrice, A. Dupraz, C. Dupuy
FULL PAPER
5 and 10 °C. After stirring at room temperature for half an hour,
the mixture was poured into 15 mL of cold water. The product
obtained was filtered, washed with diethyl ether (3 ϫ 20 mL) and
dried in vacuo for a few days to yield 27.76g (90%) of a white
powder, m.p. 136 °C. Ϫ C31H32O9S3 (644.77): calcd. C 57.66, H
the oxygens from the ether groups (TOTP or TOTA), while
the nitrogen in similar polypodal ligands does participate
in the chelation (TAHA). The presence of amino groups
enhances the stability constants of the complexes, thus pre-
venting the formation of hydroxo complexes or precipita-
tion of metal hydroxides at pH close to or above 7. The
formation of 1:1 complexes leads to a relatively high hydra-
tion number as determined by DyIII-induced 17O NMR
water shifts. A value of 5 has been obtained for the tris(car-
1
5.06; found C 57.75, H 5.00. Ϫ H NMR (CDCl3): δ ϭ 2.45 (s, 9
H, CH3), 4.18 (s, 6 H, CH2), 6.94Ϫ7.19 (m, 5 H, C6H5), 7.29 and
7.32 (d, J ϭ 7.13 Hz, 6 H, Tos-H2), 7.60 and 7.62 (d, J ϭ 6.34 Hz,
6 H, Tos-H3). Ϫ 13C NMR (CDCl3): δ ϭ 21.7 (CH3), 46.0 (C6H5-
C), 68.9 (CH2), 126.1 (C6H5-C4), 127.6 (Tos-C2), 127.9 (Tos-C3),
boxylate) ligands and a value of 2 for the tris(aminocarbox- 128.7 (C6H5-C2), 130.0 (Tos-C3), 131.6 (Tos-C4), 134.7 (C6H5-C1),
135.2 (Tos-C1).
ylate) ligands. This hydration state is expected to provide
interesting relaxivity properties for these complexes. How-
ever, the results in terms of the potentialities of these li-
gands in biomedical applications are still not satisfactory.
With some ligands of the TOTP series, the bioconjugation
1,1,1-Tris(azidomethyl)phenylmethane: 1,1,1-Tris[(4-tolylsulfonyl)-
methyl]phenylmethane (3.22 g, 5 mmol) and NaN3 (2.94 g, 45
mmol) in DMSO (50 mL) were stirred at 90 °C for three hours.
After cooling to room temperature the solution was poured into
water (250 mL). The suspension was then extracted with ethyl acet-
with a fragment of monoclonal antibody [anti-ACE(F6)]
has been realized.[2] A study of 111In radiolabelling indic- ate (250 mL). The organic fraction was washed with a saturated
ammonium chloride solution, and dried with anhydrous sodium
sulfate. The solution was filtered and the solvent was carefully re-
moved under vacuum yielding 1.471 g of a crude transparent oil
which was used directly in the following step. Ϫ 1H NMR (CDCl3):
δ ϭ 3.65 (s, 6 H, CϪCH2N3), 7.22Ϫ7.40 (m, 5 H, aromatics CH).
ated that one ligand is linked to the F(abЈ)2 but the com-
plexes of these bioconjugated polypodal ligands with 153Sm
are not stable enough to be purified.
Ϫ
13C NMR (CDCl3): δ ϭ 46.9 (C6H5-C), 54.3 (CH2), 126.2, 127.8
Experimental Section
and 128.8 (aromatics CH), 138.3 (aromatic C). Ϫ IR (NaCl disk):
νN ϭ 2103 cmϪ1
.
3
Materials: Hydrated lanthanide chlorides were obtained from Ald-
rich. All other compounds were of reagent grade and were used
without further purification.
1,1,1-Tris(aminomethyl)phenylmethane: 10% Pd/C (0.500 g) was ad-
ded to a solution of 1,1,1-tris(azidomethyl)phenylmethane (1.28 g,
5 mmol) in anhydrous ethanol (25 mL) under argon. The solution
was stirred under H2 for 6 hours and then filtered through Celite,
which was then washed with more ethanol. The solvent was re-
moved under vacuum to yield 0.075g (99%) of a transparent oil. Ϫ
C10H17N3 (179.26): calcd. C 66.66, H 9.86, N 23.25; C 67.00, H
9.56, N 23.44. Ϫ 1H NMR (CDCl3): δ ϭ 3.05 (s, 6 H, CH2),
7.19Ϫ7.42 (m, 5 H, aromatics CH). Ϫ 13C NMR (CDCl3): δ ϭ
45.4 (CH2), 48.1 (C6H5-C), 125.2, 127.1 and 128.4 (aromatics CH),
141.7 (aromatic C).
Instrumentation: 1H NMR spectra (200, 250 and 300 MHz) are
referenced to TMS and recorded on Bruker AC 200, Bruker AWM
250 or Bruker AM 300 spectrometers. 17O NMR spectra (natural
abundance) were recorded at 54.24 MHz on a Bruker AM 300 spec-
trometer, using 5 mm sample tubes. Mass spectra were obtained
with a NERMAGT1OC quadrupolar instrument. Infrared spectra
were obtained as KBr disks for solid compounds and as pure film
products between two NaCl discs for oils on a Nicolet Impact 400
spectrometer driven by the OMNIC program on a PC. Elemental
analyses were performed by Le Service Central d’Analyses du
CNRS in Vernaison (France). Melting points were measured on a
Buchi-Tottoli apparatus and are uncorrected.
1,1,1-Tris[di(tert-butylcarboxymethyl)aminomethyl]phenylmethane:
1,1,1-Tris(aminomethyl)phenylmethane (0.803 g, 4.72 mmol) was
dissolved in acetonitrile (25 mL) by warming slightly. Potassium
carbonate (7.834 g, 12 equiv.) and tert-butyl bromoacetate
(11.056g, 12 equiv.) were then added and the solution stirred for
one week at 60 °C. After cooling to room temperature the organic
products were extracted with ethyl acetate. The organic layer was
washed with saturated NaCl solution and dried with anhydrous
sodium sulfate. After filtration the solvent was removed under va-
cuum to yield a crude oil, which was purified by column chromato-
graphy with silica gel and a cyclohexane/ethyl acetate gradient from
10:0 to 8:2. The product was obtained as an oil (0.590 g, 14.5%).
Synthesis of R-TOTP and R-TOTA: These ligands were prepared
by acid hydrolysis from the corresponding polyesters, which were
themselves prepared by a previously described method.[2,3]
Synthesis of Ph-TAHA
1,1,1-Tris(hydroxymethyl)phenylmethane: A solution of phenylacet-
aldehyde (10.75 g, 0.09 mol), paraformaldehyde (16.8 g, 0.56 mol)
and Ca(OH)2 (5.2 g, 0.70 mol) in THF (60 mL) was stirred at
60Ϫ65 °C for four days. After cooling to room temperature, the
mixture was filtered through celite gel and the solvent was evapor-
ated under vacuum (0.05 Torr). The residual oil was dissolved in
hot ethyl acetate. Under standing at room temperature the product
crystallized as a white powder (9.55 g, 58%), m.p. 80Ϫ81 °C. Ϫ
C10H14O3 (182.22): calcd. C 65.32, H 7.50; found C 65.93, H 7.69.
1
MS (D/IC, NH3 ϩ isobutane): m/z ϭ 864 [M ϩ 1]ϩ. Ϫ H NMR
(CDCl3): δ ϭ 1.42 (s, 54 H, CH3), 3.23 (s, 12 H, CH2), 3.27 (s, 6
H, CH2), 7.14Ϫ7.40 (m, 5 H, aromatics CH). Ϫ 13C NMR
(CDCl3): δ ϭ 28.18 (CH3), 48.49 (C6H5-C), 56.44 (NCH2CO2tBu),
59.29 (CCH2N), 80.40 [C(CH3)3], 125.82, 126.61 and 128.55 (aro-
matics CH), 144.69 (aromatic C), 171.19 (CO2tBu).
1
Ϫ H NMR (CDCl3): δ ϭ 3.92 (s, 6 H, CH2OH), 7.18Ϫ7.46 (m, 5
H, aromatic CH). Ϫ 13C NMR (CDCl3): δ ϭ 48.7 (C6H5-C), 65.8
1,1,1-Tris[di(carboxymethyl)aminomethyl]phenylmethane:
Tris[di(tert-butyl)aminomethyl]phenylmethane (0.200g,
1,1,1-
0.232
(CH2OH), 126.7, 127.2, 129.0 and 138.4 (C6H5).
1,1,1-Tris[(4-tolylsulfonyl)methyl]phenylmethane: p-Toluenesulfonyl mmol) in formic acid (5 mL, 97%) was stirred for three hours at
chloride (36.5 g, 0.191 mol) was slowly added to a solution of 1,1,1-
tris(hydroxymethyl)phenylmethane (8.717 g, 0.048 mol) in cold pyr-
idine (90 mL) at a rate such that the temperature remained between
60 °C. The solvent was removed under vacuum and the residual
product was dried overnight under vacuum to yield 0.120 g (98%)
of product. Ϫ C22H29N3O12·3H2O (581.55): calcd. C 45.14, H 5.97,
1794
Eur. J. Inorg. Chem. 2001, 1789Ϫ1795