Silylation of hydroxyalkylidenediphosphonic acids as an effective method of their purification

Full text of DOI:10.1134/S1070363212060254

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 6, pp. 1178–1179. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.V. Lebedev, V.D. Sheludyakov, O.L. Ustinova, A.B. Lebedeva, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 6,
pp. 1044–1045.
LETTERS
TO THE EDITOR
Silylation of Hydroxyalkylidenediphosphonic Acids
as an Effective Method of Their Purification
A. V. Lebedev, V. D. Sheludyakov, O. L. Ustinova, and A. B. Lebedeva
State Scientific and Research Institute of Chemistry and Technology of Organoelemental Compounds,
sh. Entuziastov 38, Moscow, 105118 Russia
e-mail: vdsh2004@yandex.ru
Received November 21, 2011
DOI: 10.1134/S1070363212060254
As known, the silylation of hydroxyl-containing
organic compounds significantly increases their
volatility. Therefore it seemed interesting to study the
silylation of some hydroxyalkylidenediphosphonic
acids and to test the possibility of using this procedure
for a deep purification of these substances. Alkylidene-
diphosphonic acids are widely used as complex
forming agents in chemistry and medicine [1], and
significant difficulties are often met while isolating
them in a pure state [2, 3].
We have found that hydroxyalkylidenediphosphonic
acids Ia, Ib react with hexamethyldisilazane (HMDS)
to form the silylation products of four of the five
hydroxy groups, that is, tetrakistrimethylsilyl esters
IIa, IIb were obtained, according to the following scheme.
O=P(OH)2
O=P(OSiMe3)2
+
C H OH
2
5
_
_
_ _
R C OH
+ (Me Si) NH
R C OH
Ia, Ib
3
2
_NH3
_C
H
OSiMe
3
2
5
O=P(OH)2
O=P(OSiMe3)2
Ia, Ib
IIa, IIb
N
R = CH (a),
NCH (b).
2
3
Recently it was reported on the synthesis of penta-
silylated alkenylidenediphosphonic acids by the
reaction of unsaturated carboxylic acid chlorides with
tris(trimethylsilyl)phosphite [4]. The formation of
tetrasilyl derivatives in our case may be ascribed to the
decrease in the acidity of the hydroxy group on the
carbon atom due to the decrease in electron-acceptor
properties of both oxyphosphonic groups due to the
arising double bonding between the silicon and oxygen
atoms, and also to the insufficient reactivity of the
silylating agent because of this effect.
signals of protons of four trimethylsilyl groups, of hydroxy
group, and of the protons on α-carbon atom which take
part in coupling with phosphorus atoms are observed.
The synthesis of compounds IIa, IIb is complicated
by the formation of poorly soluble salts of starting
diphosphonic acids due to their reaction with liberating
ammonia. These salts decompose above 100°C with
the separation of ammonia and the liberation of
starting phosphonic acids. Due to that the reaction
requires a prolonged boiling in the excess of HMDS.
More stable compound Ia forms the silyl derivative IIa
in 85–87% yield. In the case of zoledronic acid Ib a
partial tarring of reaction mixture takes place, and the
yield of sililated compound IIb does not exceed 65%.
The structure of compounds IIa, IIb was estab-
lished from the data of elemental analysis, mass spectra,
1
1
and H NMR spectra. In the H NMR spectra the
1
178

SILYLATION OF HYDROXYALKYLIDENEPHOSPHONIC ACIDS
1179
The alcoholysis of the silyl derivative IIa with
ethanol gives spectroscopically pure acid Ia in 95%
yield. The hydrolysis of compound IIb with ethanol
containing 10% of water gives pure zoledronic acid Ib
in 97% yield.
Tetrakis(O-trimethylsilyl)hydroxyethylidenedi-
phosphonic acid (IIa). Yield 87%, bp 134–136°C
(1 mm Hg). H NMR spectrum, δ, ppm: 0.30 t (36H,
1
4SiMe ), 1.67 m (3H, CH ), 6.72 s (1H, OH). Found,
3
3
%: C 33.92, 33.78; H 8.05, 9.02. C H O P Si .
1
4
40
6
2
4
Calculated.%: C 33.99; H 8,15. Mass spectrum m/z:
+
The high value of chemical shift (δ 8.68 ppm) of
the signal of proton in the position 2 of imidazole ring
of compound Ib indicates that the zolendronic acid
molecule exists in a zwitterion form resulting in its
extremely low solubility in organic solvents and water.
A gradual addition of potassium hydroxide to the
495 [M ], calculated molecular mass 494.7306.
Tetrakis(O-trimethylsilyl)hydroxy(1-imidazolyl)-
ethylidenediphosphonic acid (IIb). Yield 65%, bp
75–177°C (0.5 mm Hg). H NMR spectrum, δ, ppm:
.29 t (36H, 4SiMe ), 5.63 t (2H, CH ), 6.52 s (1H,
OH), 6.98 s (1Harom), 7.12 s (1Harom), 7.81 s (1Harom).
Found, %: C 36.18, 36.21; H 7.52, 7.46. C H N O ·
P Si . Calculated, %: C 36.41, H 7.55. Mass spectrum,
m/z: 545 [M – CH ] , calculated molecular mass
60.7954.
1
1
0
3
2
solution of acid Ib in D O causes the appearance of
2
1
7
12
2
7
two triplets of protons of the CH group and an upfield
2
2
4
shift of the signal of proton in the position 2 of
imidazole ring (δ 7.7 ppm or less). Note that after the
addition of four equivalents of alkali to the four-basic
+
3
5
1
Alcoholysis and hydrolysis of silyl esters of
acid Ib small signal at δ 8.7 ppm remains in its H
hydroxyalkylidenediphosphonic acids. Compound
IIa, IIb, 0.1 mol, was stirred for 0.5 h in 75 ml of
ethanol or 90% aqueous ethanol respectively. After
removing of volatile substances in a vacuum in the
case of compound IIa or filtration of the precipitate
formed in the case of compound IIb pure diphosphonic
acids were obtained.
NMR spectrum which is apparently due to the low
value of the dissociation constant of the fourth hydroxy
group on phosphorus.
NMR spectra were taken on a Bruker AM-360
spectrometer in CDCl for compounds IIa, IIb, and in
3
D O for acid Ib against the residual signals of solvents
2
1
as an internal references. Mass spectra were measured
on a MAT-311A mass spectrometer at the ionizing
electrons energy 70 eV.
Zoledronic acid Ib. H NMR spectrum, δ, ppm:
4.65 t (2H, CH ), 7.33 s (1Harom), 7.48 s (1Harom), 8.67
2
s (1Harom).
REFERENCES
Silylation of hydroxyalkylidenediphosphonic
acids. A mixture of 0.1 mol of acids Ia, Ib and 0.1 mol
of HMDS was quickly heated to the temperature of
evolution of ammonia gas (about 90–100°C). At first
the mixture self-heated from 25 to 70–75°C due to the
formation of solid ammonium salts. After the begin-
ning of liberation of ammonia controlled by indicator
the mixture was slowly heated to 140°C with the
simultaneous addition of HMDS until its total amount
reached 0.4 mol. The mixture obtained was refluxed
for 1 h at 140°C and distilled in a vacuum. Target products
IIa, IIb were colleted as the last high boiling fractions.
1
2
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(
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1
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 6 2012