Synthesis of new potential chelating agents: Catechol-bisphosphonate conjugates for metal intoxication therapy

Article abstract of DOI:10.1002/hc.20013

In a quest for better chelating therapy drugs for the treatment of intoxication by Fe, Al, or actinides, three new series of bisphosphonates conjugated with catechol were synthesized.

Full text of DOI:10.1002/hc.20013

Heteroatom Chemistry
Volume 15, Number 3, 2004
Synthesis of New Potential Chelating Agents:
Catechol–Bisphosphonate Conjugates for
Metal Intoxication Therapy
Guangyu Xu, Chunhao Yang, Bo Liu, Xihan Wu, and Yuyuan Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes
for Biological Sciences, Shanghai, 201203, People’s Republic of China
Received 26 November 2003; revised 10 February 2004
well-known strong chelating properties owing to the
ABSTRACT: In a quest for better chelating ther-
formation of a three-dimensional structure capa-
ble of binding divalent metals ions such as Ca(II),
Mg(II), and Fe(II) in a bidentate manner, and the
affinity for calcium can be increased if hydroxyl
group ( OH) is attached to the geminal carbon
atom [6]. Some studies have demonstrated that
bisphosphonates also have very high affinity for
metal ions such as Cu(II) [7], Al(III), and Fe(III)
[8].
apy drugs for the treatment of intoxication by
Fe, Al, or actinides, three new series of bispho-
sphonates conjugated with catechol were synthe-
ꢀ
C
sized.
2004 Wiley Periodicals, Inc. Heteroatom Chem
15:251–257, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20013
INTRODUCTION
Catechol ligand is commonly found in the side-
rochromes, which are low-molecular-weight com-
pounds produced by microbes and involved in their
cellular iron transports [9]. Catecholate ligands in-
corporating a variety of electron-withdrawing sub-
stituents have been extensively studied for their ex-
traordinary high affinity with high oxidation state
metals such as Fe(III) [10] and actinides such as ura-
nium(IV) and thorium(IV) [11].
In recent years, a great deal of attention has been
focused on the development of more satisfactory
chelating agents for the treatment of human metal
intoxication. Accumulation of metal ions usually
causes serious diseases. For example, a number of
inherited diseases result from iron overloading [1].
Aluminum poisoning has been associated with neu-
rological dysfunction [2,3] and renal dialysis related
encephalopathy [4].
The purpose of the present investigation was to
synthesize new chelating agents 4, 8, and 13 hav-
ing mixed functional groups such as bisphosphonic
acid and catechol in order to enhance binding affin-
ity with concerned metal ions.
In this paper, we report the synthesis of new
chelating agents containing functional groups of cat-
echol and bisphosphonate.
RESULTS AND DISCUSSION
For the synthesis of new ligands 4, polybenzyloxy-
benzoyl chlorides 1 were used as starting mate-
rials. They were prepared as previously described
[12] from polyhydroxy benzoic acids (Scheme 1).
The aminoalkylenebisphosphonic acid sodium salts
2 were prepared according to Kieczykowski’s method
[13].
Bisphosphonates are widely used in the treat-
ment of various diseases of bone mineral metabolism
disorders [5]. Bisphosphonic acid ligand possesses
Correspondence to: Xihan Wu; e-mail: xhwu@mail.shcnc.ac.cn.
c
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2004 Wiley Periodicals, Inc.
251

252 Xu et al.
good yields. The amides 7 formed were then hydro-
genated in methanol at atmospheric pressure using
Pd/C as catalyst (Scheme 4). The free bisphosphonic
acids are very hydroscopic while the sodium salts are
very stable at ambient temperature.
For a comparative study, we have synthesized
another series of nitrogen-containing bisphosphonic
acids 13 incorporated with catechol linked by non-
amide bond (Schemes 5 and 6).
SCHEME 1
Compounds 12a,b were obtained by condensa-
tion of tetraethyl aminomethylbisphosphonate 10
and dihydroxybenzaldehyde 9 followed by reduction
in the presence of acetic acid with NaBH(OAc)3 pre-
pared in situ [17]. For the synthesis of 13c, benzyl-
protected dihydroxy cinnamaldehyde prepared from
caffeic acid by several steps [18,19] was used as start-
ing material. Reduction of 11c gave 12c and hy-
drogenolysis product 15.
Dealkylation of bisphosphonic ester functions
was carried out by using bromotrimethylsilane fol-
lowed by methanolysis. In this way, the free bisphos-
phonic acids were obtained in satisfactory yields and
good purity.
The benzyl-protected polyhydroxybenzoyl chlo-
ride in THF was added to a solution of monosodium
salt of aminoalkylenebisphosphonic acid in aq
NaOH. After completion of the reaction, the pH
value of the solution was adjusted to acidic. The
monosodium salt of bisphosphonic acid was ob-
tained when the pH was lower than 2, while dis-
odium salt 3 was obtained when the pH was between
3 and 4 (Scheme 2). The hydrogenolysis of benzyl-
protected polyhydroxybenzoylaminoalkanebisphos-
phonates 3 was carried out in water with Pd/C as
catalyst. The product bisphosphonates 4 were pre-
cipitated from aqueous solution by addition of alco-
hol (Scheme 2). The length of the methylene chain
and the number of phenolic groups can be varied
as desired with stable yields. This method avoided
the acid breakage of the amide bond in the synthesis
of phosphonate [14] and bisphosphonate derivatives
[15].
In summary, three types of 1,1-bisphosphonic
acids bearing catechol moiety were efficiently pre-
pared in satisfactory yields. Data on the chelating po-
tency of the new bisphosphonates will be published
elsewhere.
We next directed our efforts to the synthesis of
ligand 8, and the desired 3,3-bis(dibenzyloxyphos-
phoryl)propanoic acid 5 [16] was prepared from
tetraethyl methylenebisphosphonate (Scheme 3).
Coupling reaction of amine 6 with tetraben-
zyl bisphosphonate 5 was carried out in THF at
room temperature, using isobutyl chloroformate and
N-methylmorpholine (NMM) as coupling agents in
EXPERIMENTAL SECTION
Melting points were determined using a Bu¨chi
510 melting point apparatus and are uncorrected.
1
NMR, H (400.13 MHz), 13C (100.61 MHz), and 31P
(161.99 MHz), spectra were recorded on a Bruck-400
NMR spectrometer with TMS as an internal standard
(1H and 13C) and 85% H3PO4 as an external standard
SCHEME 2

Synthesis of New Potential Chelating Agents 253
6-N-(3,4-Dibenzyloxybenzoyl)aminohexane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (3b)
80.3%, White powder, mp > 300◦C, 1H NMR
(NaOD/D2O): δ 1.22 (m, 2H, CH2), 1.40–1.47 (m,
4H, CH2CH2CP2), 1.70–1.80 (m, 2H, CH2CH2N),
3.19 (t, J = 7.0 Hz, 2H, CH2N), 5.04 (s, 2H,
PhCH2O), 5.06 (s, 2H, PhCH2O), 6.96–7.28 (m, 13H,
Ph-H); 31P NMR (D2O): δ 18.87; Anal. calcd for
C27H31NNa2O10P2·2.5H2O: C, 47.51; H, 5.32; N, 2.05.
Found: C, 47.44; H, 5.44; N, 2.19.
SCHEME 3
(31P). Mass spectra were obtained on a MAT-95 spec-
trometer. Microanalysis were carried out on a Leco
CHN-2000 elemental analyzer.
5-N-(2,3-Dibenzyloxybenzoyl)aminopentane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (3c)
73.2%, White powder, mp > 300◦C, 1H NMR (NaOD/
D2O): δ 1.41 (m, 2H, CH2), 1.48–1.56 (m, 2H,
CH2CP2), 1.72–1.82 (m, 2H, CH2CH2N), 3.11 (t, J =
7.7 Hz, 2H, CH2N), 4.93 (s, 2H, PhCH2O), 5.13 (s, 2H,
PhCH2O), 6.96–7.44 (m, 13H, Ph-H); 31P NMR (D2O):
δ 19.32; Anal. calcd for C26H29NNa2O10P2·3H2O: C,
46.09; H, 5.21; N, 2.07. Found: C, 45.89; H, 5.34; N,
2.01.
4-N-(2,3-Dibenzyloxybenzoyl)aminobutane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (3a)
2,3-Dibenzyloxybenzoyl chloride (23.5 g, 66.7 mmol)
in THF (24 ml) was added dropwise to a stirred
solution of (4-amino-1-hydroxybutylidene)bisphos-
phonic acid monosodium salt (10.0 g, 30.8 mmol)
in aq NaOH (3.5%, 180 ml, 158 mmol) at 5◦C. Af-
ter the addition was complete (30 min), the result-
ing mixture was allowed to warm to room tem-
perature (rt), and stirred for an additional 6 h;
aq. HCl (1.0 mol/l) was added until the pH of
the solution reached 4. The precipitate was filtered
with suction, washed with acetone (450 ml), water
(150 ml), and acetone (450 ml), and the pure product
was obtained by recrystallization from EtOH/H2O,
dried at 60◦C for 24 h to give 16.58 g (81.2%
3-N-(3,4,5-Tribenzyloxybenzoyl)aminopropane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (3d)
1
40.5%, White needle, mp > 300◦C, H NMR (NaOD/
D2O): δ 2.00–2.08 (m, 2H, CH2), 3.45 (t, J = 7.8
Hz, 2H, CH2N), 4.95 (s, 2H, PhCH2O), 5.23 (s, 4H,
PhCH2O), 7.27–7.60 (m, 17H, Ph-H); 31P NMR (D2O):
δ 19.96; Anal. calcd for C31H31NNa2O11P2·4H2O: C,
48.13; H, 5.08; N, 1.81. Found: C, 48.21; H, 4.97; N,
1.89.
1
yield) of white solid of 3a. mp > 300◦C, H NMR
(NaOD/D2O): δ 1.78–1.82 (m, 2H, CH2), 1.88–1.92 (m,
2H, CH2CP2), 3.19 (t, J = 7.2 Hz, 2H, CH2N), 5.01
(s, 2H, PhCH2O), 5.21 (s, 2H, PhCH2O), 7.05–7.52
(m, 13H, Ph-H); 31P NMR (D2O): δ 19.12; Anal. calcd
for C25H27NNa2O10P2·3H2O: C, 45.26; H, 5.01; N, 2.11.
Found: C, 45.21; H, 4.97; N, 2.20. Compounds 3b–d
were prepared using the method described for the
preparation of 3a.
4-N-(2,3-Dihydroxybenzoyl)aminobutane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (4a)
A suspension of 3a (8.42 g, 12.8 mmol) in water
(50 ml) was combined with Pd/C (10%, 4.5 g) and
SCHEME 4

254 Xu et al.
SCHEME 5
hydrogenated at rt for 2 days; the mixture was
then vacuum filtered from catalyst. The debenzy-
lated product 4a was purified by precipitating it
from aq solution by addition of ethanol (450 ml);
the white precipitate after drying in vacuo at 40◦C
for 24 h weighed 5.16 g (87.4% yield). mp > 300◦C,
1H NMR (D2O): δ 1.88–2.02 (m, 4H, CH2CH2CP2),
3.38 (t, J = 6.8 Hz, 2H, CH2N), 6.83 (t, J = 8.1 Hz,
1H, Ph-H), 7.03 (d, J = 8.1 Hz, 1H, Ph-H), 7.22 (d,
J = 8.1 Hz, 1H, Ph-H); 13C NMR (D2O): δ 26.1, 33.7,
42.7 (3s, CH2), 76.3 (t, JCP = 135 Hz, CP2), 118.4,
120.8, 121.4, 121.6, 146.6, 149.4 (6s, Ar-C), 172.2
(C(O)N); 31P NMR (D2O): δ 18.9; Anal. calcd for
C11H15NNa2O10P2·2H2O: C, 28.40; H, 4.12; N, 3.01.
Found C, 28.37; H, 4.14; N, 2.92; Compounds 4b–d
were prepared using the method described for the
preparation of 4a.
1.94–2.04 (m, 2H, CH2CH2N), 3.40 (t, J = 6.6 Hz, 2H,
CH2N), 7.00 (d, J = 8.4 Hz, 1H, Ph-H), 7.28 (d, J =
8.4 Hz, 1H, Ph-H), 7.33 (s, 1H, Ph-H); 31P NMR (D2O):
δ 18.12; Anal. calcd for C13H19NNa2O10P2: C, 34.15; H,
4.19; N, 3.06. Found: C, 34.39; H, 4.39; N, 3.24.
5-N-(2,3-Dihydroxybenzoyl)aminopentane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (4c)
1
84.3%, White powder, mp > 300◦C, H NMR (D2O):
δ 1.58–1.62 (m, 4H, CH2CH2CP2), 1.93–1.96 (m, 2H,
CH2), 3.36 (t, J = 6.6 Hz, 2H, CH2N), 6.81 (t, J = 8.1
Hz, 1H, Ph-H), 7.01 (d, J = 8.1 Hz, 1H, Ph-H), 7.17
(d, J = 8.1 Hz, 1H, Ph-H); 31P NMR (D2O): δ 18.54;
Anal. calcd for C12H17NNa2O10P2·1.5H2O: C, 30.65; H,
4.29; N, 2.98. Found: C, 30.87; H, 4.20; N, 2.89.
3-N-(3,4,5-Trihydroxybenzoyl)aminopropane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (4d)
6-N-(3,4-Dihydroxybenzoyl)aminohexane-1-
hydroxy-1,1-bisphosphonic Acid Disodium (4b)
1
88.8%, White powder, mp 255◦C (decom.), H NMR
1
83.6%, White powder, mp > 300◦C, H NMR (D2O):
(D2O): δ 2.20–2.28 (m, 2H, CH2), 3.68 (t, J = 7.0 Hz,
2H, CH2N), 6.96 (s, 2H, Ph-H); 31P NMR (D2O): 19.44;
δ 1.43 (m, 2H, CH2), 1.64–1.69 (m, 4H, CH2CH2CP2),
SCHEME 6

Synthesis of New Potential Chelating Agents 255
Anal. calcd for C10H13NNa2O11P2·H2O: C, 26.74; H,
3-Oxo-3-[(2,3-dihydroxyphenyl)amino]propane-
1,1-bisphosphonic Acid Disodium (8a)
3.37; N, 3.12. Found: C, 26.79; H, 3.44; N, 2.98.
To a solution of compound 9a (170 mg, 0.193 mmol)
in absolute methanol (8 ml) was added 10% Pd/C
(110 mg) and the resulting suspension was hydro-
genated for 48 h at rt; the catalyst was removed
by filtration and washed thoroughly with methanol
(ca 2 ml), the combined solution was evaporated
in vacuo, and the residue was triturated with aq
NaHCO3 (0.5%, 3.24 ml) to give 54.2 mg (71.3% yield)
of white solid. mp > 300◦C, 1H NMR (D2O): δ 2.78 (tt,
1H, J = 6.8, 21.8 Hz, CHP2), 2.94 (td, J = 6.8, 15.0
Hz, 2H, CH2), 6.84–6.91 (m, 3H, Ph-H); 13C NMR
(D2O): δ 35.2 (s, CH2), 38.4 (t, JCP = 105 Hz, CP2,),
117.0, 120.4, 122.5, 126.6, 141.6, 147.3 (6s, Ph-C),
175.9 (NHC O); 31P NMR (D2O): δ 19.6; Anal. calcd.
For C9H11NNa2O9P2·0.5H2O: C, 27.43; H, 3.07; N,
3.55. Found: C, 27.81; H, 3.37; N, 3.44. Compounds
8b and 8c were prepared using the method described
for the preparation of 8a.
Tetrabenzyl 3-Oxo-3-[(2,3-dibenzyloxyphenyl)-
amino]propane-1,1-bisphosphonate (7a)
To a solution of 3,3-bis(dibenzyloxyphosphoryl)-
propanoic acid (355 mg, 0.597 mmol) in dry THF
(5.5 ml) was added N-methylmorpholine (70 mg,
0.693 mmol), followed by isobutyl chloroformate
(94.6 mg, 0.693 mmol) at −10◦C; a sticky solid
formed, and the mixture was left at −8◦C for 20 min.
To the mixture was added 210 mg of 2,3-dibenzyloxy-
benzamine (0.688 mmol) and stirring was continued
at room temperature for 30 min. Ice water (25 ml)
was added, extracted with chloroform (25 ml), the or-
ganic phase was washed with saturated NaHCO3 (2 ×
5 ml), aq HCl (2.0 mol/L, 2 × 5 ml), water (2 × 10 ml),
and dried with Na2SO4. After removal of solvent, the
residue gum was purified by chromatography on a
silica-gel column (mobile phase PE/EtOAc from 3:2
to 1:1) to provide 300 mg (57.0%) of colorless oil
1
of 7a. H NMR(CDCl3): δ 2.63 (td, 2H, J = 5.6, 16.6
3-Oxo-3-[(3,4-dihydroxyphenyl)amino]propane-
1,1-bisphosphonic Acid Disodium (8b)
Hz, CH2), 3.54 (tt, 1H, J = 5.6, 24.0 Hz, CH), 4.82
(s, 2H, PhCH2O), 4.96–5.09 (m, 8H, 4 × POCH2Ph),
1
mp > 300◦C, White powder, 74.1%, H NMR (D2O):
5.16 (s, 2H, PhCH2O), 6.75–7.88 (m, 33H, Ph-H); 31
P
δ 2.82 (tt, 1H, J = 6.6, 20.8 Hz, CHP2), 3.07 (td,
2H, J = 6.6, 15.6 Hz, CH2), 7.08 (d, J = 8.4 Hz,
1H, Ph-H), 7.14 (d, J = 8.4 Hz, 1H, Ph-H), 7.30 (s,
1H, Ph-H); 31P NMR (D2O): δ 19.3; Anal. calcd for
C9H11NNa2O9P2·1.5H2O: C, 26.23; H, 3.42; N, 3.40.
Found C, 26.51; H, 3.59; N, 3.11.
NMR (CDCl3): δ 13.87; Anal. calcd for C51H49NO9P2:
C, 69.46; H, 5.60; N, 1.59. Found C, 69.33; H, 5.91;
N, 2.01. Compounds 7b and 7c were prepared using
the method described for the preparation of 7a.
Tetrabenzyl 3-Oxo-3-[(3,4-dibenzyloxyphenyl)-
amino]propane-1,1-bisphosphonate (7b)
3-Oxo-3-[2-(3,4-dihydroxyphenyl)ethylamino]-
propane-1,1-bisphosphonic Acid Disodium (8c)
Colorless oil, 63.3%, 1H NMR(CDCl3): δ 2.91 (td,
2H, J = 5.9, 16.8 Hz, CH2), 3.42 (tt, 1H, J =
5.9, 24.2 Hz, CHP2), 4.93–5.11 (m, 12H, PhCH2O,
4 × P(O)CH2Ph), 7.18–7.43 (m, 33H, Ph-H); 31P NMR
(CDCl3): δ 14.32; Anal. calcd for C51H49NO9P2: C,
69.46; H, 5.60; N, 1.59. Found C, 69.12; H, 5.13; N,
1.44.
1
mp > 300◦C, White powder, 76.8%, H NMR (D2O):
δ 2.53 (tt, 1H, J = 5.6, 22.1 Hz, CHP2), 2.70 (td, 2H,
J = 5.6, 16.8 Hz, CH2CHP2), 2.75 (t, J = 7.1 Hz, 2H,
PhCH2), 3.43 (t, J = 7.1 Hz, 2H, CH2N), 6.78 (d, J =
8.1 Hz, 1H, Ph-H), 6.88 (s, 1H, Ph-H), 6.92 (d, J = 8.1
Hz, 1H, Ph-H); 31P NMR (D2O): δ 19.7; Anal. calcd
for C11H15NNa2O9P2·H2O: C, 30.64; H, 3.97; N, 3.25.
Found: C, 30.59; H, 4.30; N, 3.02.
Tetrabenzyl 3-Oxo-3-[2-(3,4-dibenzyloxyphenyl)-
ethylamino]propane-1,1-bisphosphonate (7c)
Colorless oil, 70.1%, 1H NMR (CDCl3): δ 2.53(t,
J = 6.9 Hz, 2H, PhCH2), 2.64 (td, J = 5.9, 16.5
Hz, 2H, CH2CHP2), 3.27 (q, 2H, CH2NH), 3.41 (tt,
J = 5.9, 24.3 Hz, 1H, CHP2), 4.93–5.07 (m, 8H,
4 × POCH2Ph), 5.13 (s, 4H, 2 × PhCH2O), 6.60 (d,
J = 8.2 Hz, 1H, Ph-H), 6.71 (s, 1H, Ph-H), 6.82 (d,
Tetraethyl (E)-N-(2,3-dihydroxybenzylidene)-
aminomethylbisphosphonate (11a)
2,3-Dihydroxybenzaldehyde (345 mg, 2.5 mmol) was
added to a solution of tetraethyl aminomethylbis-
phosphonate (758 mg, 2.5 mmol) in dry benzene
(25 ml) and the mixture was heated at reflux in a
Dean-stark for 4 h. The solvent was evaporated at re-
duced pressure and the crude product was purified
by crystallization from ethyl acetate and petroleum
J = 8.2 Hz, 1H, Ph-H), 7.22–7.46 (m, 30H, Ph-H); 31
P
NMR (CDCl3): δ 14.56; Anal. calcd for C53H53NO9P2:
C, 69.96; H, 5.87; N, 1.54. Found C, 69.56; H, 6.18;
N, 1.63.

256 Xu et al.
ether (1:1) to provide the pure compound as yel-
low crystal (81.6% yield). mp 131–133.5◦C, 1H NMR
(DMSO-d6): δ 1.19 (m, 12H, 4 × CH3), 4.07 (m, 8H,
4 × CH2), 4.83 (t, J = 19.0 Hz, 1H, CHP2), 6.73–6.92
N, 3.29. Found: C, 45.77; H, 6.88; N, 3.25. Compound
12b was prepared using the method described for the
preparation of 12a.
4
(m, 3H, Ph-H), 8.60 (t, 1H, JPH = 3.9 Hz, CH N),
Tetraethyl N-(3,4-dihydroxyphenylmethyl)-
aminomethylbisphosphonate (12b)
9.2 (s, 1H, Ph-OH), 12.53 (s, 1H, Ph-OH). 31P NMR
(DMSO-d6): δ 18.09, Anal. calcd. For C16H27NO8P2: C,
45.39; H, 6.43; N, 3.31. Found: C, 45.59; H, 6.31; N,
3.29. Compounds 11b and 11c were prepared using
the method described for the preparation of 11a.
1
Pale yellow crystal, 70.2%, mp 89–92◦C, H NMR
(CDCl3): δ 1.32 (m, 12H, 4 × CH3), 3.46 (t, 1H,
J = 21.4 Hz, CHP2), 3.94 (s, 2H, CH2N), 4.18 (m,
8H, 4 × CH2), 6.66 (d, J = 8.2 Hz, 1H, Ph-H), 6.80
(d, J = 8.2 Hz, 1H, Ph-H), 7.00 (s, 1H, Ph-H), 31P
NMR (DMSO-d6): δ 17.64; MS: m/z 425 (M+ − 1,
13), 138 ((OH)2PhCH2NH+, 47); Anal. calcd. For
C16H29NO8P2: C, 45.18; H, 6.87; N, 3.29. Found: C,
45.73; H, 6.75; N, 3.16.
Tetraethyl (E)-N-(3,4-dihydroxybenzylidene)-
aminomethylbisphosphonate (11b)
1
Orange crystal, 88.4%, mp 140.5–142◦C, H NMR
(DMSO-d6): 1.20 (m, 12H, 4 × CH3), 4.06 (m, 8H,
4 × CH2), 4.52 (t, 1H, J = 18.6 Hz, CHP2), 6.78–
4
7.24 (m, 3H, Ph-H), 8.19 (t, 1H, JPH = 4.03 Hz,
Tetraethyl N-[3-(3,4-dihydroxyphenylpropyl)-
amino]methylbisphosphonate (12c)
CH N); 31P NMR (DMSO-d6): δ 18.77; Anal. calcd.
For C16H27NO8P2: C, 45.39; H, 6.43; N, 3.31. Found:
C, 45.67; H, 6.43; N, 3.17.
To a solution of tetraethyl (E)-N-[3-(3,4-dibenzyl-
oxyphenylprop-2-enylidene) amino]methylbisphos-
phonate (300 mg, 0.477 mmol) in ethyl acetate was
added Pd/C (10%, 150 mg), the mixture was con-
ducted in a hydrogen steam at rt under atmospheric
pressure for 4 h. The catalyst was removed by fil-
tration and the filtrate was evaporated under vac-
uum. The crude residue was purified by flash chro-
matography eluting with ethyl acetate/methanol 60:1
to yield 170 mg (78.8%) of 12c as a pale yellow oil. 1H
NMR (DMSO-d6): δ 1.22 (m, 12H, 4 × CH3), 1.57 (m,
2H, CH2CH2CH2), 2.38 (t, J = 7.4 Hz, 2H, PhCH2),
2.67 (t, J = 7.1 Hz, 2H, CH2N), 3.33 (t, 1H, J = 20.2
Hz, CHP2), 4.03 (m, 8H, 4 × CH2), 6.39 (d, J = 8.0
Hz, 1H, Ph-H), 6.53 (s, 1H, Ph-H), 6.59 (d, J = 8.0
Hz, 1H, Ph-H), 8.58 (s, 1H, Ph-OH), 8.66 (s, 1H, Ph-
OH); 31P NMR(DMSO-d6): δ 17.60; Anal. calcd. For
C18H33NO8P2: C, 47.68; H, 7.34; N, 3.09. Found: C,
47.73; H, 7.55; N, 2.98.
Tetraethyl (E)-N-[3-(3,4-dibenzyloxyphenylprop-
2-enylidene)amino]methylbisphosphonate (11c)
White crystal, 71.7%, mp 93–95◦C, 1H NMR (DMSO-
d6): δ 1.20 (m, 12H, 4 × CH3), 4.06 (m, 8H, 4 × CH2),
4.60 (t, 1H, J = 18.8 Hz, CHP2), 5.17 (s, 2H,
PhCH2O), 5.19 (s, 2H, PhCH2O), 6.91–7.47 (m, 15H,
Ph-H, CH CH), 8.10 (m, 1H, CH N), 31P NMR
(DMSO-d6): δ 18.62; Anal. calcd. For C32H41NO8P2:
C, 61.04; H, 6.56; N, 2.22. Found: C, 61.20; H, 6.56;
N, 2.10.
Tetraethyl N-(2,3-dihydroxyphenylmethyl)-
aminomethylbisphosphonate (12a)
Glacial acetic acid (2.96 ml) was added dropwise
to NaBH4 (128 mg, 3.39 mmol) under N2 atmo-
sphere and the resulting solution was stirred at
rt until evolution of hydrogen gas ceased. Then
dry acetonitrile (5 ml) was added and cooled
to 0◦C, the imine 11a (529 mg, 1.2 mmol) was
added in one portion and stirred for 1 h at 0◦C.
Acetic acid and acetonitrile were removed at re-
duced pressure and the crude product was purified
by flash chromatography eluting with ethyl ac-
etate/methanol (25:1–15:1) to provide the pure com-
pound 11a as pale yellow crystal (377 mg, 70.9%).
N-(2,3-Dihydroxyphenylmethyl)aminomethyl-
bisphosphonic Acid (13a)
Trimethylsilyl bromide (0.65 ml, 4.92 mmol) was
added dropwise to a solution of bisphosphonate 12a
(147 mg, 0.346 mmol) in dry acetonitrile (4 ml) at 5◦C
under an N2 atmosphere. The mixture was stirred
at rt for 2 days and the solvent was evaporated off
to give a yellow oil. Methanol (20 ml) was added
to give a white precipitate, the purified product as
a white powder was obtained by recrystallization
from methanol (106 mg, yield 95.1%), mp 217–219◦C
(decom.), 1H NMR(D2O): δ 3.49 (t, 1H, J = 18.1
Hz, CHP2), 4.60 (s, 2H, CH2N), 6.90 (t, J = 8.0 Hz,
1H, Ph-H), 6.96 (d, J = 7.7 Hz, 1H, Ph-H), 7.03 (d,
1
mp 115–117.5◦C, H NMR (CDCl3): δ 1.22 (m, 12H,
4 × CH3), 3.54 (t, 1H, J = 22.1 Hz, CHP2), 3.88 (s,
2H, CH2N), 4.05 (m, 8H, 4 × CH2), 6.55–6.67 (m, 3H,
Ph-H), 31P NMR (DMSO-d6): δ 17.33; MS: m/z 166
(NH2CHP(O)(OEt)2+, 100), 138 ((OH)2PhCH2NH+,
76). Anal. calcd. For C16H29NO8P2: C, 45.18; H, 6.87;

Synthesis of New Potential Chelating Agents 257
J = 7.7 Hz, 1H, Ph-H); 13C NMR(NaOD/D2O): δ 54.1
(s, CH2), 56.3 (t, JCP = 113 Hz, CP2), 118.8, 119.9,
125.2, 125.8, 146.5, 147.4 (6s, Ph-C); 31P NMR (D2O):
δ 8.26; Anal. calcd. For C8H13NO8P2·0.5H2O: C, 29.83;
H, 4.38; N, 4.35. Found: C, 29.93; H, 4.74; N, 4.09.
Compounds 13b,c were prepared using the method
described for the preparation of 13a.
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Stolowich, N. J.; Kline, S. J. J Org Chem 1983, 48,
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N-(3,4-Dihydroxyphenylmethyl)aminomethyl-
bisphosphonic Acid (13b)
1
89.1%, White powder, mp 190◦C (decom.), H NMR
(D2O): δ 3.58 (t, J = 18.7 Hz, 1H, CHP2), 4.42 (s,
2H, CH2N), 6.94–7.04 (m, 3H, Ph-H); 31P NMR
(D2O): δ 8.06; Anal. calcd. For C8H13NO8P2·1.5H2O:
C, 28.25; H, 4.74; N, 4.12. Found: C, 28.02; H, 5.00;
N, 3.97.
N-[3-(3,4-Dihydroxyphenylpropyl)amino]-
methylbisphosphonic Acid (13c)
1
84.3%, White powder, mp 229–231◦C (decom.), H
NMR (D2O): δ 2.05 (m, 2H, CH2CH2CH2), 2.67 (t, J =
7.5 Hz, 2H, PhCH2), 3.42 (t, J = 7.9 Hz, 2H, CH2N),
3.55 (t, 1H, J = 18.5 Hz, CHP), 6.78 (d, J = 8.2 Hz,
1H, Ph-H), 6.88 (s, 1H, Ph-H), 6.91 (d, J = 8.2 Hz,
1H, Ph-H); 13C NMR (NaOD/D2O): 30.2, 33.6, 51.0
(3s, CH2), 57.1 (t, JCP = 120 Hz, CP2), 118.6, 118.7,
123.0, 136.0, 144.4, 146.2 (6s, Ph-C); 31P NMR (D2O):
δ 8.22; Anal. calcd. For C10H17NO8P2: C, 35.20; H,
5.02; N, 4.11. Found: C, 35.00, H, 5.21, N, 4.15.
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