The rational synthesis of fenidronate

Article abstract of DOI:10.2174/1570178611666140124001516

The synthesis of the disodium salt of fenidronate by the reaction of benzoic acid with phosphorus trichloride and phosphorous acid in methanesulfonic acid was investigated and optimized. It was enough to use 3.2 equivalents of phosphorus trichloride and t

Full text of DOI:10.2174/1570178611666140124001516

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368
Letters in Organic Chemistry, 2014, 11, 368-373
The Rational Synthesis of Fenidronate
Alajos Grün1, Rita Kovács1, Dávid Illés Nagy1, Sándor Garadnay2, István Greiner2 and
György Keglevich1,*
1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest,
Hungary; 2Gedeon Richter Plc., 1475 Budapest, Hungary
Received December 13, 2013: Revised January 15, 2014: Accepted January 16, 2014
Abstract: The synthesis of the disodium salt of fenidronate by the reaction of benzoic acid with phosphorus trichloride
and phosphorous acid in methanesulfonic acid was investigated and optimized. It was enough to use 3.2 equivalents of
phosphorus trichloride and there was no need to apply phosphorous acid. Both the one-step and two-step versions led to
similar results giving the product in ca. 45% yield and in high purity. It was also possible to start directly from benzoyl
chloride or ethyl benzoate. The work-up included in all cases hydrolysis and pH adjustment followed by purification. The
fenidronic acid standard that was necessary for the analysis of our samples was prepared by another approach, by the
addition of dimethyl phosphite to the carbonyl group of the ꢀ-oxophosphonate, followed by hydrolysis of the tetramethyl
ester so formed.
Keywords: Dronic acid, dronate, synthesis, intermediate, optimization, titration.
1. INTRODUCTION
also possible to accomplish the addition step under
microwave conditions [17, 18].
C-substituted-1-hydroxy-1,1-bisphosphonic acids are
efficient drugs used against bone diseases, such as
osteoporosis, hypercalcemia, osteolytic metastases and the
Paget disease [1-5]. The 1-hydroxy-geminal bisphosphonic
acids have a tridentate functionality to enable the binding of
Ca2+ ions and to promote the affinity for species responsible
for the accumulation of phosphates in the bone tissues [1-9].
Based on the reaction of the corresponding 1-substituted
acetic acid and phosphorus trichloride, we elaborated the
rational synthesis of risedronate and zoledronate [19, 20], as
well as ibandronate and alendronate [21]. Etidronate was
also prepared in this way [22]. According to our method,
only 3.2 equivalents of phosphorus trichloride were used and
there was no need to apply phosphorous acid as the other
reagent. We were the first, who selected the reactants
consciously, on the basis of the mechanism envisaged [23].
In respect of fenidronate, there was, in the first approach, a
similar procedure described [11] that has been revisited by
us now.
There are two major methods for the preparation of C-
substituted-1-hydroxy-1,1-bisphosphonic acids. The first and
more widely applied method involves the reaction of a
suitable carboxylic acid with phosphorus trichloride and
phosphorous acid (or only with phosphorus trichloride) [10].
This method was also applied for the synthesis of
fenidronate [11].
2. RESULTS AND DISCUSSION
According to another approach, fenidronic acid was
synthesized by the Arbuzov-reaction of benzoyl chloride
with tris(trimethylsilyl)phosphite as the first step. Addition
of a second molecule of tris(trimethylsilyl)phosphite on the
carbonyl unit of the ꢀ-oxophosphonate intermediate so
formed followed by migration of a trimethylsilyl group and
finally methanolysis afforded fenidronic acid [12-14]. This
synthesis was carried out also from benzoic acid using
catecholborane as an activator [15]. Another possibility for
the synthesis of fenidronic acid involves the addition of
dialkyl phosphite on the carbonyl carbon of dialkyl
benzoylphosphonate [16]. Acidic hydrolysis of the resulting
tetraalkyl ester gives rise to the bisphosphonic acid [16]. It is
To be able to analyze our fenidronate samples, first we
had to prepare fenidronic acid as the standard. The best
approach was to form dimethyl benzoylphosphonate 1 by the
Arbuzov reaction of benzoyl chloride and trimethyl
phosphite and to add dimethyl phosphite on the carbonyl
group of the intermediate (1) formed. Acidic hydrolysis of
the tetramethyl ester (2) so formed afforded fenidronate (3)
(Scheme 1) [16].
In the first experiments we applied the phosphorus
trichloride and phosphorous acid reactants in different ratios
in reaction with benzoic acid in methanesulfonic acid (MSA)
as the solvent at 75 °C for 1 day (Scheme 2). The reactions
were followed by hydrolysis at 105 °C for 4 h, and then by
pH adjustment by 50% NaOH/H2O to 1.8. The crude
fenidronic disodium salt (4) was obtained by precipitation
using MeOH. Further purification comprised two additional
precipitations from water solution and finally an extraction
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary;
Tel: 36-1-463-1 I I 1/5883; Fax: 36-1-463-3648;
E-mails: gkeglevich@mail.bme.hu and gkeglevich@gmail.com
1875-6255/14 $58.00+.00
© 2014 Bentham Science Publishers

The Rational Synthesis of Fenidronate
Letters in Organic Chemistry, 2014, Vol. 11, No. 5 369
O
(MeO)2P(O)H
0 ꢀ 26 °C
O
O
0 ꢀ 26 °C
P
OMe
(MeO)3P
+
diethylether
OMe
Cl
1
OH
OH
O
O
O
O
105 °C / 3h
cc. HCl
MeO
P
P
OMe
OMe
HO
HO
P
P
OH
OH
MeO
3
2
Scheme 1.
(digestion) of the solid product with MeOH at the boiling
point to remove all impurities.
The main impurity of crude fenidronate was MeSO3Na
formed in reaction of MSA with NaOH. Purification of the
crude product including two precipitations (from water
solution) by methanol followed by digestion of the solid
product in methanol was useful in removing the impurity. As
a result, in the better experiments (Table 1/Entries 3 and 4),
fenidronate (4) was obtained with a dronate content ꢀ94%
according to potentiometric acid-base titration.
The use of only 3.2 equivalents of phosphorous acid did
not lead to the formation of the expected product (4) (Table
1/Entry 1). By decreasing the quantity of phosphorous acid
to 2.1 and 1.1 equivalents, and at the same time increasing
the proportion of phosphorus trichloride to 1.1 and 2.1
equivalents, fenidronate 4 was obtained in a yield of 13%
and 36%, respectively. In the latter cases, the dronate (4)
content was 74% and 94%, respectively, on the basis of
potentiometric titration (Table 1/Entries 2 and 3). The
dronate (4) content was also determined by 31P NMR
analysis. In the latter two cases, the purity was 70% and
92%, respectively; these values are comparable with those
obtained by titration. In the instance, when only 3.2
equivalents of phosphorus trichloride was used as the P-
reagent (and no phosphorous acid was added), the yield of
product 4 was 46%, while the dronate (4) content was in
average 98.5% (Table 1/Entry 4). It can be seen that the best
results were achieved, when phosphorus trichloride was the
sole P-reagent, and when it was used in a 3.2 equivalent
quantity. As in earlier cases [19,21,22], the phosphorous
acids was not found to be of sufficient nucleophilicity.
Our attempt to reproduce the procedure of Russian
authors [11], who claimed to have synthesized fenidronate
by the solvent-free reaction of benzoic acid and phosphorus
trichloride, failed. Work-up of the heterogeneous reaction
mixture furnished solely phosphorous acid. Not even traces
of fenidronate (4) could be detected in the reaction mixture.
It was assumed that the first step towards the dronate
formation, involves the conversion of the carboxylic acid to
the corresponding acid chloride by reaction with 1 equivalent
of phosphorus trichloride [23]. In methanesulfonic acid
solvent, a mixed anhydride RC(O)O(O)2SMe (5) may also be
formed from the acid chloride and a molecule of solvent.
Hence, in the synthesis of fenidronate, benzoyl chloride
and/or PhC(O)O(O)2SMe (6) may be the first intermediate.
To prove this, an experiment was carried out in which
benzoic acid was reacted with 1.1 equivalents of phosphorus
trichloride in methanesulfonic acid in the first step. In the
second step, the intermediates (benzoyl chloride and
anhydride 6) formed were reacted with 2.1 equivalents of
phosphorus trichloride at 75 °C for 18 h that was followed
by hydrolysis and other steps shown above (Scheme 3). In
this case, product 4 was obtained in a yield of 43% with an
average dronate content of 97.5% (Table 2/Entry 1). It can
be seen that the one- and two-step procedures had rather
similar outcomes (Table 1/Entry 4 vs. Table 2/Entry 1). In
1) 75 °C/1 day
PCl3ꢀH3PO3 (3.2 equiv.)
ONa
OH
OH
ONa
OH
MeSO3H
2) 105 °C/4 h
H2O
O
P
P
O
3) 50% NaOH/H2O ꢁ pH 1.8
4) MeOH
OH
O
4
Scheme 2.
Table 1. Synthesis of Fenidronate.
Reactants
Purity (%)
Entry
Yield of 4 (%)a,b
On the Basis of
PCl3 (equiv.)
H3PO3 (equiv.)
On the Basis of 31P NMRa
Potentiometric Titrationa
1
2
3
4
0
3.2
2.1
1.1
0
-
-
0
1.1
2.1
3.2
70
92
97
74
13
36
46
94
100
aFrom at least two parallel experiments.
bOn the basis of the titration.

370 Letters in Organic Chemistry, 2014, Vol. 11, No. 5
Grün et al.
1) 75 °C / 18 h
PCl3 (2.1 equiv.)
MeSO3H
2) 105 °C / 4 h
H2O
O
ONa
OH
OH
ONa
OH
PCl3 or SOCl2
or (Cl3CO)2CO
(1.1 equiv.)
O
P
P
Cl
O
and/or
MeSO3H
OH
3) 50% NaOH / H2O ꢀ pH 1.8
4) MeOH
O
O
O
O
S
O
4
Me
6
Scheme 3.
Table 2. Synthesis of Fenidronate in Two Steps.
Purity (%)a
Inorg. halide
(1.1 equiv.)
P-reactant
(2.1 equiv.)
Entry
Yield of 4 (%)a,b
On the Basis of 31P NMRa
On the Basis of Titrationa
1
2
3
4
PCl3
PCl3
PCl3
H3PO3
PCl3
97
-
98
76
97
-
43
~10
26
0
SOCl2
SOCl2
94
-
H3PO3
aFrom at least two parallel experiments.
bOn the basis of the titration.
another experiment, the in situ formed intermediates
(benzoyl chloride and 6) were reacted with 2.1 equivalents of
phosphorous acid. In this case, dronate 4, was formed in an
insufficient purity (76%) and in a low yield of ca. 10%
(Table 2/Entry 2). The experiment carried out with thionyl
chloride in the first step was quite successful, when
phosphorus trichloride was used in the second step (Table
2/Entry 3), but remained without result, when phosphorous
acid was the reagent in the second step (Table 2/Entry 4).
In the last experiment, ethyl benzoate was reacted with
2.2 equivalents of phosphorus trichloride under the
conditions applied in the previous experiments (75 °C/24h)
(Scheme 4, Y = EtOH). Product 4 was obtained with a
dronate content of 94%, in a yield of 36%. The outcome
shows resemblance to that of the experiment with benzoyl
chloride.
One can conclude that it has some effect on the outcome
if fenidronate (4) is synthesized from benzoic acid, benzoyl
chloride or ethyl benzoate using phosphorus trichloride. We
proved that the synthesis of fenidronate may be performed
best from benzoic acid using 3.2 equivalents of phosphorus
trichloride as the P-reagent. It is also possible to carry out the
synthesis in two steps applying 1.1 equivalents of
phosphorus trichloride or thionyl chloride in the first step,
and then 2.1 equivalents of phosphorus trichloride in the
second step. Starting from benzoyl chloride or ethyl
benzoate, the yields of fenidronate 4 were somewhat lower,
but starting from benzoyl chloride, the purity was 100%.
Regarding the synthesis of dronates, the yields related to
pure products are rarely higher than 46-53% [19,21]. This is
caused by the relatively high proportion of the impurities and
the rather complex purification procedure. Hence, our yields
of 46/43% for fenidronate (4) in respect to the best
experiments are quite reasonable.
In the next variation, benzoyl chloride was chosen as the
starting material that was reacted with 2.2 equivalents of
phosphorus trichloride under the conditions applied above
(75 °C/24h) (Scheme 4, Y = Cl). This experiment gave
product 4 with a dronate content of 100%, in a yield of 35%.
This result is not so far from that obtained in the reaction of
benzoic acid with 3.2 equivalents of phosphorus trichloride
(Table 1/Entry 4).
3. EXPERIMENTAL
3.1. General
31P NMR spectra were obtained on a Bruker AV-300
spectrometer at 121.50 MHz; chemical shifts are downfield
relative to 85% H3PO4. The fenidronate content of the
samples was determined by potentiometric acid-base
titrations on a Mettler DL77 potentiometric titrator.
1) 75 °C/1 day
PCl3
MeSO3H
2) 105 °C/4 h
H2O
O
4
3) 50% NaOH/H2O ꢀ pH 1.8
Y
4) MeOH
The titration curve for pure fenidronic acid synthesized
by us and for that of the sample obtained from the reaction
marked by (Table 1/Entry 4) are shown in Figs. 1 and 2,
respectively.
Y = Cl, EtO
Scheme 4.

The Rational Synthesis of Fenidronate
Letters in Organic Chemistry, 2014, Vol. 11, No. 5 371
O
P
O
ONa
OH
ONa
O
P
O
HO
NaO
ONa
OH
OH
P
OH
HO
HO
Ph
Ph
P
OH
Ph
Ph
P
P
P
O
HO
HO
P
HO
ONa
ONa
HO
O
O
ONa
OH
O
Fig. (1). Titration curve for fenidronic acid.
O
O
P
ONa
ONa
OH
HO
NaO
P
OH
Ph
Ph
P
P
HO
HO
ONa
ONa
O
O
Fig. (2). Titration curve for the disodium salt of fenidronic acid obtained by the reaction marked by (Table 1/Entry 4).
3.2. Preparation of Fenidronic Acid with the Michaelis-
Arbuzov Reaction [17]
Then, 3.0 g (9.0 mmol) of the tetramethyl ester was
hydrolyzed by refluxing with 20 ml concentrated HCl for 3
h. The solvent was removed under reduced pressure to
furnish 2.4 g (99%) of the fenidronic acid (3). 31P NMR
(D2O) ꢀ: 16.0, ꢀ [16]: 15.5. 1H NMR (D2O) ꢀ: 7.64 -7.61 (m,
2H, ArH), 7.32 -7.24 (m, 3H, ArH), ꢀ [15] 7.65-7.62 (m, 2H,
ArH), 7.32-7.22 (m, 3 H, ArH).
5.8 ml (0.05 mol) of benzoyl chloride was placed in a
reaction flask and cooled to 0 °C. Then 5.9 ml (0.05 mol) of
trimethyl phosphite was added dropwise with rapid stirring.
After the addition was completed, the reaction mixture was
allowed to warm up to 26 °C and then the crude product was
distilled in vacuum to afford 6.0 g (56%) of dimethyl
benzoylphosphonate (1) as a yellow oil (bp 142 °C (5 Torr),
bp [16] 130-134 °C (3 Torr), bp [17] 154-156 °C (8 Torr)).
3.3. Preparation of the Disodium Salt of Fenidronate (4)
Starting from Benzoic Acid in a One Step Reaction
(Table 1/Entry 4)
2.3 ml (25 mmol) of dimethyl phosphite and 0.33 ml (1.3
mmol) of dibuthylamine were dissolved in 50 ml of diethyl
ether and the solution was cooled to 0 °C. Then, 5.0 g (23.0
mmol) of dimethyl benzoylphosphonate (1) was added
dropwise. A white solid precipitated. The reaction mixture
was allowed to warm to 26 °C and the solid was filtrated to
yield 6.0 g (40%) of fenidronic acid tetramethyl ester (2). 31P
NMR (CDCl3) ꢀ: 18.3, ꢀ [16]: 18.0, ꢀ [17]: 18.4.
3.1 g (0.025 mol) of benzoic acid was added into 10.5 ml
of MSA on stirring. Then 7.0 ml (0.08 mol) of phosphorus
trichloride was added dropwise in ca. 30 min, and the
contents of the flask were stirred at 75 °C for 24 h. After
cooling the mixture to 26 °C, 25 ml (1.4 mol) of water was
added and the mixture was stirred further at 105 °C for 4 h.
The pH was adjusted to 1.8 by adding ~12 ml of 50%

372 Letters in Organic Chemistry, 2014, Vol. 11, No. 5
Grün et al.
3.7. Preparation of Fenidronate Disodium Salt (4) from
Ethyl Benzoate
aqueous sodium hydroxide to the mixture. Then 127 ml of
methanol was added, the mixture stirred for 45 min and the
precipitate was removed by filtration. The crude product was
dissolved in 10 ml of hot water and 50 ml of methanol was
added, then the precipitate was filtered off and dried to give
13.3 g of fenidronate disodium salt (4) in a purity of ca. 67%
(on the basis of 31P NMR). The precipitation was repeated
twice by adding 50 ml of methanol to the 10 ml water
solution of the crude product. Then the solid product was
suspended in the 50 ml mixture of methanol-water 94:6 and
the mixture was digested by stirring at 65 °C for 30 min,
then the solid product was filtered off. This procedure was
repeated twice to afford 3.6 g (46%) of fenidronate disodium
salt (4) in a purity of 100%. 31P NMR (D2O) ꢀ: 16.0, ꢀ[15]
16.39, 13C NMR (D2O) ꢀ: 136.9 (t, J=2.3, C1), 128.1 (t,
J~2.1, C3*), 127.4 (t, J~2.1, C4), 126.0 (t, J = 4.4, C2*), 76.5
(t, J = 140.9, P-C-P), ꢀ [24] 135.7, 128.1, 127.7, 125.8,
75.7 (t, J = 145.1), *may be reversed.
3.6 ml (0.025 mol) of ethyl benzoate was dissolved in
10.5 ml of methanesulfonic acid on stirring. 4.8 ml (0.055
mol) of phosphorus trichloride was added dropwise and the
mixture was stirred at 75 °C for 24 h. Further processment
including hydrolysis, pH adjustment and precipitation with
MeOH was performed as described above to give 3.0 g
(36%) of fenidronate disodium salt (4) in a purity of 94%.
31P NMR (D2O) ꢀ: 16.6.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
The research was supported by Gedeon Richter Plc and
by Hungarian Scientific and Research Fund (OTKA
K83118).
3.4. Preparation of Fenidronate Disodium Salt (4)
Applying Phosphorus Trichloride in a Two Step Reaction
(Table 2/Entry 1)
3.1 g (0.025 mol) of benzoic acid was dissolved in 10.5
ml of methanesulfonic acid on stirring. 2.3 ml (0.026 mol) of
phosphorus trichloride was added dropwise and the mixture
was stirred at 26 °C for 6 h. Then, 4.8 ml (0.055 mol) of
phosphorus trichloride was added dropwise and the mixture
was stirred at 75 °C for 18 h. Further processing including
hydrolysis, pH adjustment and precipitation with MeOH was
performed as described above to afford 14,1 g of crude
product. After the two precipitations with MeOH and three
digestions with MeOH/water 94:6 carried out similarly as
above, 3.4 g (43%) of fenidronate disodium salt (4) was
obtained in a purity of 98%. 31P NMR (D2O) ꢀ: 16.7.
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