A study on the synthesis of risedronic acid: The role of an ionic liquid additive

Article abstract of DOI:10.2174/1570180815666180626122630

Background: The synthesis of high value risedronic acid is not fully resolved, as, for the time being, the best method based on the preparation from 3-pyridylcarboxylic acid by reaction with phosphorus trichloride in methanesulfonic acid gives risedronic acid in a good yield, but in an unpure form. Methods: Alternative protocols realizing the synthesis in sulfolane as the solvent and/or in the presence of suitable IL additive were developed to obtain the target dronic acid in a pure form. Results & Conclusion: Using phosphorus trichloride and phosphorous acid in two equivalents quantities together with 0.6 equivalents of [bmim][BF4] without any solvent, the method afforded the target dronic acid in a yield of 66% in a pure form.

Full text of DOI:10.2174/1570180815666180626122630

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Letters in Drug Design & Discovery, 2018, 15, 1-7
1
RESEARCH ARTICLE
A Study on the Synthesis of Risedronic Acid; The Role of an Ionic Liquid
Additive
Dávid Illés Nagy1, Alajos Grün1, Júlia Sinkovicz1, 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
Abstract: Background: The synthesis of high value risedronic acid is not fully resolved, as, for the
time being, the best method based on the preparation from 3-pyridylcarboxylic acid by reaction
with phosphorus trichloride in methanesulfonic acid gives risedronic acid in a good yield, but in an
A R T I C L E H I S T O R Y
unpure form.
Received: March 02, 2018
Revised: May 11, 2018
Accepted: May 17, 2018
Methods: Alternative protocols realizing the synthesis in sulfolane as the solvent and/or in the pres-
ence of suitable IL additive were developed to obtain the target dronic acid in a pure form.
DOI:
Results & Conclusion: Using phosphorus trichloride and phosphorous acid in two equivalents
10.2174/1570180815666180626122630
quantities together with 0.6 equivalents of [bmim][BF4] without any solvent, the method afforded
the target dronic acid in a yield of 66% in a pure form..
Keywords: Risedronic acid, 3-pyridylacetic acid, P-reagents, sulfolane, ionic liquid additive, optimization.
1. INTRODUCTION
acid and/or their salts) together with the mechanisms for
their formation have been reviewed and summarized by us
[10]. The most preferred solvent in the preparation of dronic
acid derivatives is methanesulfonic acid (MSA). In most
syntheses of risedronic acid and its sodium salt, 3-
pyridylacetic acid (1) served as starting carboxylic acid [11].
Selected preparations of risedronic acid (2) derivatives utiliz-
ing phosphorus trichloride and phosphorous acid were sum-
marized in Table 1. Beside these P-reagents, phosphoryl
chloride or phosphorus trioxide was also applied using 3-
pyridylacetic acid in MSA. The reaction of heteroaryl acetic
acid 1 with 2.1 equivalents of phosphorus trichloride and 1
equivalent of phosphorous acid in MSA furnished risedronic
acid (2) in a yield of 38%, but no purity criterion was pro-
vided (Table 1/Entry 1) [12]. Using phosphorus trichloride
and phosphorous acid in a molar ratio of 2:3 in a 1:3 mixture
of MSA-diethyl carbonate as the solvent, risedronate (2-Na)
was obtained in a yield of 73%. A purity of 99.9% was
claimed that was established by HPLC (Table 1/Entry 2)
[13]. However, the unusually good outcome for product 2-
Na based on a complete purity may be questionable due to
the considerable portion of the ballast represented by the
excess of phosphorous acid (see later), and the Na salt of
MSA formed from a part of the solvent on pH adjustment by
NaOH. The inorganic impurities mentioned cannot be seen
by HPLC. Our reproductive experiments showed that under
the conditions described, the yield was even higher (89%),
but the purity was only 82%. Using only 3.2 equivalents of
phosphorus trichloride as the P-reagent in MSA, risedronic
acid (2) was obtained in a yield of 74%, and in a purity of
1-Hydroxy-methylenebisphosphonic (dronic) acid deriva-
tives have two phosphonate groups connected to the same
carbon atom. They are efficient drugs against bone diseases,
such as osteoporosis, the Paget-disease, tumor-induced hy-
percalcaemia and osteolytic bone metastases. On the one
hand, the dronic derivatives inhibit bone resorption, on the
other hand, they have direct antitumor and antiparasitic ac-
tivity [1-3]. The 1-hydroxy-geminal bisphosphonic acids
have a tridentate functionality to enable the binding of Ca2+
ions, and thus to promote their accumulation in the bone
mineral. The hydroxy group on the central carbon atom in-
creases the affinity to the Ca2+ ions. The C-substituent on the
methylene unit also has a significant impact on the biological
activity. The first generation of dronic acid derivatives does
not bear a nitrogen atom in the side chain, while the mem-
bers of the second and third generation have an aminoalkyl
or an N-heterocyclic substituent, respectively. These N-
containing derivatives have a more significant biological
effect. Risedronic acid is one of the most important and effi-
cient members of the third generation of hydroxy-
methylenebisphosphonic derivatives [1-9]. Syntheses of the
major representatives of dronic derivatives (pamidronic acid,
alendronic acid, ibandronic acid, zoledronic acid, risedronic
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and Eco-
nomics, 1521 Budapest, Hungary; E-mail: gkeglevich@mail.bme.hu
1570-1808/18 $58.00+.00
©2018 Bentham Science Publishers

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Letters in Drug Design & Discovery, 2018, Vol. 15, No. 0
OH
Nagy et al.
and phosphorous acid in different quantities (1.5-3.5:1.5-3.5
equivalents). The yields fell in the range of 52–96%, but
these data are not reliable at all, as they refer to crude prod-
ucts [18-22]. A typical example is shown in (Table 1/Entry 6)
[20].
O
1) 80 °C/3 h
PCl3 (3.1 equiv.)
P
OH
P
O
HO
OH
OH
MSA
2) H2O/!
3) pH=2
O
N
HO
1
N
The synthesis of the target molecule was also carried out
in toluene as the solvent [23]. In these instances, phosphoryl
chloride and in the dronate discipline unusual reagents, for
example, propylphosphonic anhydride (T3P), methanesulfo-
nic acid anhydride or phosphorus pentachloride were used
together with phosphorous acid in different ratios. Crude
risedronic acid (2) was prepared in a yield of 58-90%, in
claimed purities of around 98% [23]. These days, there is a
demand to use more environmentally-friendly reagents and
solvents in organic chemical syntheses. Ionic liquids (ILs)
are considered green solvents, due to their low vapor pres-
sure, high thermal stability, and recyclability. In addition,
they are fine-tuneable solvents, as their properties including
lipophilicity and polarity may be adjusted by selecting the
appropriate cations and anions. It is a new tendency that the
ILs are applied as only an additive or a catalyst in syntheses,
and not as a solvent [24-30]. This approach was utilized by
us in the preparation of a few important dronic acid deriva-
tives, such as pamidronic acid [27], alendronate [28], iban-
dronate [29] and zoledronic acid [30]. The synthesis of hy-
droxy-methylenebisphosphonic acid derivatives was hardly
performed in ILs as solvents; the preparation of risedronic acid
was attempted in an IL only once. Reacting 3-pyridylacetic acid
(1) with the mixture of 2 equivalents of phosphorus trichloride
and 1 equivalent of phosphorous acid in tributylammonium
chloride as the medium, a low yield of 12% was reported for
crude risedronic acid (2) (Table 1/Entry 7) [31].
2
Scheme (1). Preparation of risedronic acid (2) in MSA by an opti-
mized method [11].
92% (Scheme 1) (Table 1/Entry 3) [11]. It was clarified by
us that phosphorous acid is unnecessary, when phosphorus
trichloride is applied in MSA as the solvent [11]. However,
the preparation of pure risedronic acid from reaction mix-
tures containing MSA as the medium is complicated by the
presence of MeSO3Na.
In another case, when MSA was the solvent and 2
equivalents of phosphoryl chloride and 3 equivalents of
phosphorous acid were the P-reagents, risedronic acid was
obtained in a yield of 55% in a purity of 98% [14]. Carrying
out the synthesis with 3 equivalents of phosphorus trioxide
and 3.5 equivalents of phosphorous acid, a similar yield of
54% was claimed) [15].
Sulfolane is also a preferred solvent during the prepara-
tion of hydroxy-methylenebisphosphonic acid derivatives,
but in the case of risedronate, this was a less used medium.
McKenna and his co-workers reacted 3-pyridylacetic acid (1)
with 3-3 equivalents of phosphorus trichloride and phospho-
rous acid in sulfolane under MW conditions. The crude rise-
dronic acid (2) was obtained in a yield of 74% without purity
criterions (Table 1/Entry 4) [16]. In another instance, phos-
phorus trichloride and phosphorous acid were applied in a
ratio of 3.4:1.5 to afford risedronate in a yield of 54%. The
purity of the product was 99% (Table 1/Entry 5) [17].
Generally, dronic acid derivatives cannot be synthesized
in good yields in the absence of any solvent. However, rise-
dronic acid could be prepared under solvent-free conditions,
and quite good yields were claimed, but without providing
purity criterions. The majority of the researchers applied
The preparation of risedronic acid derivatives was also
performed in chlorobenzene using phosphorus trichloride
Table 1. Selected Preparations of Risedronic Acid (2) Derivatives Utilizing Phosphorus Trichloride and Phosphorous Acid as the
P-reagents in Different Solvents.
Entry
Solvent
Reactants (equiv.)
Product Form
Purity (%)
Yield
Refs.
1
2
MSA
PCl3 : H3PO3 (2.1:1)
PCl3 : H3PO3 (2:3)
PCl3 (3.1)
acid
Na*2.5H2O
acid
-
38
73(89)3
74
[12]
[13]
[11]
[16]
[17]
[20]
[31]
[32]
[34]
[35]
MSA1
99.92 (82)3,4
3
MSA
1004
4
sulfolane
PCl3 : H3PO3 (3:3)
PCl3 : H3PO3 (3.4:1.5)
PCl3 : H3PO3 (2.4:2.4)
PCl3 : H3PO3 (2:1)
PCl3 : H3PO3 (5:3)5
PCl3 : H3PO3 (2:1.5)
PCl3 : H3PO3 (2.5:2.2)
acid*H2O
Na
-
99
842
-
745
54
5
sulfolane
6
chlorobenzene
acid
58
7
[Bu3NH][Cl]
acid
26
8
-
-
-
Na
-
86
9
acid
67
10
Na*2.5H2O
99,92
65
1in 1:3 mixture of MSA and diethyl carbonate. 2On the basis of HPLC. 3Our reproduction. 4On the basis of acid-base titration. 5 Under MW conditions.

A Study on the Synthesis of Risedronic Acid
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 0
3
phosphorus trichloride and phosphorous acid as the P-
reagents in molar ratios of 2:1.5 – 5:5. The crude product
was isolated in yields of 65–86% (Table 1/Entries 8-10) [32-
35]. In a special combination, phosphoryl chloride and phos-
phorous acid were used in an unnecessarily large excess of
3.2:9.7 affording dronic acid 2 in a yield of 60% [36].
of 3.4 mL of MSA and 10.2 mL of diethyl carbonate on stir-
ring. Then, 4.4 mL (0.05 mol) of phosphorus trichloride was
added dropwise in ca. 30 min and the contents of the flask
were stirred at 69 °C for 6 h. After cooling the mixture to 25
°C, 17 mL (0.94 mol) of water was added, and the mixture
was stirred further at 105 °C for 5.5 h. The contents of the
flask were cooled to 70 °C, and 17 mL isopropanol was
added. Next, the mixture was cooled to 10 °C, and the pH
was adjusted to 1.8 by adding ~12 mL of 50% aqueous so-
dium hydroxide. Then, the suspension was stirred further at
the same temperature for 1 h, and the precipitate was re-
moved by filtration, washed with 5 mL isopropanol, and
finally dried. The crude risedronic acid obtained was added
to 120 mL of water on stirring. Next, the mixture was cooled
to 15 °C, and the pH was adjusted to 4.9 by adding 50%
aqueous sodium hydroxide. The mixture was stirred at the
same temperature for 15 min, and after the addition of 1 g of
activated carbon for 20 min. The carbon was removed by
filtration, washed with 20 mL of water, then the solution was
cooled to 15 °C, and 20 mL of isopropanol was added, and
the mixture stirred at 15 °C for 2 h, then at 0–5 °C for 1 h.
120 mL of cold isopropanol was added, and the contents of
the flask were stirred at 0–5 °C for 2 h. The solid precipitate
was filtered off, transferred to another flask, and suspended
in a mixture of 60 mL of water and 60 mL of isopropanol,
and the suspension stirred at 15 °C for 40 min. The solid
phase was removed by filtration, washed with the mixture of
cold isopropanol (5 mL) and cold water (5 mL), and dried to
give 9,5 g (89%) of the monosodium salt of risedronic acid
as a hemi(pentahydrate) in a purity of 82%. According to the
patent [13], the product was claimed to have been isolated in
a yield of 73%, and in a purity of 99.9%.
Synthesis of the dronic acid under discussion was inves-
tigated in a series of other solvents (e.g. in acetonitrile [20,
37], n-octane [38, 39], ethyl acetate [23], dioxane [38],
diphenyl ether [40], phenol derivatives [41] or diethyl car-
bonate [13] etc.) as well. However, in the lack of practical
importance, these procedures are peripheral.
After the successful precedents in case of other dronic
acid derivatives [27-30], we wished to develop an efficient
and up-to-date synthesis of the high value (£ 160/g), third
generation hydroxy-methylenebisphosphonic acid, risedronic
acid (2) in sulfolane as the medium, and/or in the presence of
an IL additive. The methods applying MSA as the solvent
have the shortcoming of providing risedronic acid (2) in an
unpure form.
2. EXPERIMENTAL
2.1. General
1
31P, 13C and H NMR spectra were obtained on a Bruker
AV-300 spectrometer operating at 121.50 MHz, 75.5 MHz
and 500 MHz, respectively. Chemical shifts are downfield
relative to 85% H3PO4 or TMS. The couplings are given in
Hertz. The risedronic acid (3) content of the samples was
determined by potentiometric acid-base titrations on a Met-
tler DL77 potentiometric titrator.
The titration curve for the risedronic acid (3) obtained from
the reaction marked by Table 3/Entry 2 is shown in Fig. (1).
2.3. Preparation of Risedronic Acid Monohydrate (3)
from 3-Pyridylacetic Acid (1), Phosphorus Trichloride
and Phosphorous Acid in Sulfolane (Table 2/Entry 3)
2.2. Reproduction of the Procedure of Vakamudi et al.
for the Preparation of the Monosodium Salt of Rise-
dronic Acid Hemi(pentahydrate) [13]
1.7 g (0.013 mol) of 3-pyridylacetic acid (1) and 2.2 g
(0.027 mol) of phosphorous acid were added into 5 mL of
sulfolane on stirring. Then, 2.5 mL (0.029 mol) of phospho-
rus trichloride was added dropwise in ca. 30 min, and the
contents of the flask were stirred at 75 °C for 3 h. After cool-
3.4 g (0.025 mol) of 3-pyridylacetic acid (1) and 6.1 g
(0.074 mol) of phosphorous acid were added into the mixture
Fig. (1). Titration curve for the risedronic acid (3) obtained by the reaction presented in Table 3/Entry 2.

4
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 0
Nagy et al.
OH
ing the mixture to 25 °C, 10 mL (0.56 mol) of water was
added, and the mixture was stirred further at 105 °C for 1 h.
Then, the solution was stirred at 0–5 °C for 3 h, and the pre-
cipitate was removed by filtration to give ~3 g of the crude
product that was suspended in 30 mL of methanol, and the
mixture was digested by stirring at 65 °C for 30 min. The
solid product was filtered off to furnish 2.2 g (58%) of rise-
dronic acid monohydrate (3) in a purity of 100%. 31P NMR
(D2O) δ: 17.1, δ [42]: 18.1; 1H NMR (D2O) δ: 3.31–3.23 (t, J
= 12.0, 2H, CH2), 7.54 (dd, J = 7.8 J = 5.6, 1H, NCHCH),
8.17 (d, J = 8.0, 1H, NCHCHCH), 8.32 (d, J = 5.2 1H,
NCH), 8.52 (s, 1H, NCHC), δ [42]: 3.26 (t, J = 12.1, 2H),
7.55 (dd, J = 8.2, 5.5, 1H), 8.18 (d, J = 5.5, 1H), 8.32 (d, J =
5.5, 1H), 8.51 (s, 1H); 13C NMR (D2O) δ: 36.3 (s, CH2), 73.6
(t, J = 130.7, P-C-P), 124.7 (s, NCHCH), 136.4 (t, J = 8.5 C),
142.1 (s, NCHCHCH), 144.8 (s, NCH), 146.2 (s, NCHC), δ
[42]: 36.5, 73.8, 125.3, 137.1, 141.3, 145.3, 146.1.
O
x H2O
P
OH
1) 75 °C/3 h
PCl3/P(OH)3
O
HO
OH
OH
P
sulfolane
O
N
HO
2) 105 °C/1 h
H2O
3) crystallization
4) MeOH digestion
1
N
3
Scheme (2). Preparation of risedronic acid (3) in sulfolane.
Table 2. Synthesis of risedronic acid (3) from 3-pyridylacetic
acid (1) in sulfolane using phosphorus trichloride
and phosphorous acid in different ratios.
Reactants
Entry
Purity (%)a,b Yield of 3b
PCl3 (equiv.) H3PO3 (equiv.)
2.4. Preparation of Risedronic Acid Monohydrate (3)
from 3-Pyridylacetic Acid (1), Phosphorus Trichloride
and Phosphorous Acid in the Presence of [bmim][BF4]
(A), or in Sulfolane in the presence of [bmim][BF4] Addi-
tive (B) (Table 3/Entry 2, Table 4/Entry 1)
1
2
3
4
5
6
7
8
9
2
2
0
1
2
3
4
0
1
2
3
98
98
2
39
58
60
57
4
2
100
100
98
2
2.5 mL (0.029 mol) of phosphorus trichloride was added
dropwise into the mixture of 1.7 g (0.013 mol) of 3-
pyridylacetic acid (1), 2.2 g (0.027 mol) of phosphorous acid
and 1.4 mL (0.008 mol) of [bmim][BF4] (A), or into the mix-
ture of 5 mL of sulfolane and 1.4 mL (0.008 mol) of
[bmim][BF4] (B) on stirring in ca. 30 min, and the contents
of the flask were stirred at 75 °C for 3 h. Further processing
including hydrolysis, crystallization and digestion was per-
formed as described above (Chapter 4.3) to afford 2.5 g
(66%, (A), Table 2/Entry 2) and 2.5 g (65%, (B), Table
3/Entry 1) of risedronic acid monohydrate (3) in a purity of
100% and 99%, respectively. 31P NMR (D2O) δ: 17.2 and
17.1 respectively, δ [42]: 18.1.
2
3.2
3
100
100
100
100
29
49
51
3
3
aOn the basis of potentiometric titration. bFrom at least five parallel experiments.
2–4% (Table 2/Entries 1 and 6). Using a 2:1 mixture of
phosphorus trichloride and phosphorous acid, the product (3)
was obtained in a yield of 39% (Table 2/Entry 2). Repeating
the experiments with 2, 3 and 4 equivalents of phosphorous
acid, the yields were 58%, 60% and 57%, respectively (Ta-
ble 2/Entries 3–5). As practically similar results (ca. 59%
yields) were obtained, the best molar ratio of the P-reagents
is 2:2. Applying phosphorus trichloride in a quantity of 3.2
equivalents together with 1, 2 and 3 equivalents of phospho-
rous acid, risedronic acid (3) was obtained in yields of 29%,
49% and 51%, respectively (Table 2/Entries 7-9). It can be
seen that the results of the experiments with 3 equivalents of
phosphorus trichloride (Table 2/Entries 7-9) are more mod-
est, than those with 2 equivalents of this reagent (Table
2/Entries 2-4). It is also evident that the earlier yield of 54%,
obtained in sulfolane using phosphorus trichloride and phos-
phorous acid in quantities of 3.4 and 1.5 equivalents [17],
could be improved by us to 58% by the application of the P-
reagents in a ratio of 2:2 that is better than the results ob-
tained in MSA, as refers to pure product [11].
3. RESULTS AND DISCUSSION
3.1. Syntheses of Risedronic Acid in Sulfolane
In the first series of experiments, the preparation of rise-
dronic acid (3) by the reaction of 3-pyridylacetic acid (1)
with phosphorus trichloride and phosphorous acid in sulfo-
lane (Scheme 2) was optimized. The reaction was carried out
with different ratios of the P-reagents. After a stirring at 75
°C for 3h, the mixture was hydrolyzed at 105 °C. On cool-
ing, the target dronic acid (3) precipitated, and the crystals
were removed by filtration. The final purification involved
an extractive boiling with methanol. The purity was deter-
mined by potentiometric acid-base titration, NMR measure-
ments, as well as HPLC. The shape of the curve in the acid-
base titration diagram suggests the form of the product (if it
is acid or a kind of salt), and the results of the titration de-
termine the total dronic derivative content. The other impuri-
ties may be detected by 31P and 13C NMR, as well as HPLC
measurements. Experimental data were summarized in Table 1.
3.2. Syntheses of Risedronic Acid in the Presence of an
Ionic Liquid
It can be seen that using phosphorus trichloride alone in
sulfolane, no matter if the P-reagent was measured in a 2 or
3.2 equivalents’ quantity, risedronic acid 3 (containing 1
molecule of crystalline water) was formed in low yields of
According to our earlier experiments, ILs as additives
promoted the efficient syntheses of dronic acid derivatives,
pamidronic acid, ibandronate and zoledronic acid [27, 29,

A Study on the Synthesis of Risedronic Acid
Letters in Drug Design & Discovery, 2018, Vol. 15, No. 0
5
1) 75 °C/3 h
PCl3/P(OH)3
1) 75 °C/3 h
PCl3/P(OH)3
3
3
1
1
IL additive
sulfolane and IL additive
2) 105 °C/1 h
H2O
2) 105 °C/1 h
H2O
3) crystallization
4) MeOH digestion
3) crystallization
4) MeOH digestion
Scheme (3). Preparation of risedronic acid (3) in the presence of an
Scheme (4). Preparation of risedronic acid (3) in sulfolane using an
ionic liquid.
ionic liquid additive.
30]. This was also tried in the synthesis of risedronic acid
[bmim][BF4] led to comparable results (Table 4/Entries 1
(Scheme 3).
and 2) with those obtained without sulfolane.
Measuring in the P-reagents in a quantity of 2–2 equiva-
lents, and applying [bmim][BF4] in portions of 0.9, 0.6 and
0.3 equivalents, risedronic acid 3 was obtained in yields of
58%, 66% and 51%, respectively (Table 3/Entries 1, 2 and
4). As earlier [27-30], with increasing quantities of the IL
additive, the yields followed a curve with a maximum. The
presence of 0.6 equivalents of [bmim][BF4] was the optimum
promoting a record yield of 66%. Applying phosphorus
trichloride and phosphorous acid in a ratio of 3:2 at a 0.6 and
0.3 equivalents quantity of the IL, the yields were 65% and
60%, respectively (Table 3/Entries 3 and 5). As a blind probe
comparison, one of the above experiments was also per-
formed in the absence of [bmim][BF4] to provide a lower
yield of 35% (Table 3/Entry 6). Another IL, [bmim][PF6]
was also tested as an additive at a 2:2 ratio of the P-reagents.
The presence of 0.6 and 0.3 equivalents of the IL led to
yields of 57% and 51%, respectively. The preparation of
risedronic acid (3) seems to be more advantageous in the
presence of [bmim][BF4] as an additive, than in sulfolane or
MSA as the solvents. This statement is justified by the yields
of 66%, 58% and 59%, respectively. Moreover, the solvent-
free accomplishments are always preferable.
One may see that the use sulfolane is unnecessary when
[bmim][BF4] additive is applied in the synthesis under dis-
cussion.
It is clear that from the variations investigated, the route
utilizing the P-reagents in a 2 equivalents quantity in the
presence of 0.6 equivalents of [bmim][BF4] is the most ap-
propriate. This protocol furnishes risedronate in a yield of
66% in an entirely pure form. This approach is better than a
previous one realizing the synthesis in MSA in the presence
of 3.2 equivalents of phosphorus trichloride to afford the
target dronic acid in a purity of only 92%, and in a yield of
74% [11], as the quantity of the dronic acid is very similar in
both cases (0.66x1 ≈ 0.74x 0.92), however, there is no need
for an additional purification in the new procedure.
It is interesting to compare the best set of parameters for
the more important dronic acid derivatives. The methods are
similar but significantly different. E.g. for ibandronate [29],
at a 3:2 ratio of phosphorus trichloride and phosphorous
acid, in the presence of 0.1 equivalents of [bmim][BF4], a
yield of 90% was reported for a pure product. The optimum
conditions for zoledronic acid involved a 2:2 ratio of the P-
reagents, and the use of 0.3 equivalents of the same IL.
However, in this case, there was a need for sulfolane as the
solvent. In this way, pure zoledronic acid was obtained in a
yield of 89% [30]. As regards risedronic acid [present paper],
at a molar ratio of 2:2, in the presence of 0.6 equivalents of
the IL, a maximum yield of 66% could be achieved for pure
compound, moreover in the absence of sulfolane.
3.3. Syntheses of Risedronic Acid in Sulfolane in the
Presence of an Ionic Liquid Additive
Finally, the preparation of risedronic acid (3) was at-
tempted in sulfolane as the solvent together with an IL addi-
tive (Scheme 4, Table 4). As can be seen, the use of
Table 3. Synthesis of Risedronic Acid (3) from 3-Pyridylacetic Acid (1) in the Presence of [bmim][BF4] Additive Using Phosphorus
Trichloride and Phosphorous Acid in Different Ratios.
Reactants
Entry
Amount of [bmim][BF4] (equiv.)
Purity (%)a,b
Yield of 3b
PCl3 (equiv.)
H3PO3 (equiv.)
1
2
3
4
5
6
0.9
0.6
2
2
3
2
3
2
2
2
2
2
2
2
99
58
66
65
51
60
35
100
100
100
100
100
0.3
0
aOn the basis of potentiometric titration. bFrom at least five parallel experiments.

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Letters in Drug Design & Discovery, 2018, Vol. 15, No. 0
Nagy et al.
Table 4. Synthesis of Risedronic Acid (3) from 3-Pyridylacetic Acid (1) in Sulfolane in the Presence of 0.6 Equivalents of
[bmim][BF4] or [bmim][PF6] Using Phosphorus Trichloride and Phosphorous Acid in Different Ratios.
Reactants
Entry
Type of IL
Purity (%)a,b
Yield of 3b
PCl3 (equiv.)
H3PO3 (equiv.)
1
2
3
2
3
2
2
2
2
99
100
95
65
67
49
[bmim][BF4]
[bmim][PF6]
aOn the basis of potentiometric titration. bFrom at least five parallel experiments.
Bisphosphonates inhibit breast and prostate carcinoma cell
invasion, an early event in the formation of bone metastases.
Cancer Res., 2000, 60, 2949-2954.
Reid, I. R.; Miller, P.; Lyles, K.; Fraser, W.; Brown, J. P.; Saidi,
Y.; Mesenbrink, P.; Su, G.; Pak, J.; Zelenakas, K.; Luchi, M.;
Richardson, P.; Hosking, D. Comparison of a single infusion of
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CONCLUSION
In conclusion, the high-value drug, risedronic acid used
in the treatment of bone deceases could be prepared from 3-
pyridylacetic acid applying two equivalents of the P-reagents
(phosphorus trichloride and phosphorous acid) in the ab-
sence of any solvent, using only 0.6 equivalents of
[bmim][BF4] as a catalytic additive. The optimized method
afforded the target dronic acid in a yield of 66% in a pure
form. This method is more advantageous than the previous
protocol applying 3.2 equivalents of phosphorus trichloride
in MSA as the solvent that furnishes risedronic acid in a bet-
ter yield (74%) but in a purity of only 92%.
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Chhipa, N. M. R.; Sen, D. J. Aminobiphosphonates in osteoporosis:
A Review. Int. J. Drug. Dev. Res., 2013, 5, 120-132.
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Nagy, D. I.; Grün, A.; Greiner, I.; Keglevich, G. The role of
phosphorus trichloride and phosphorous acid in the formation of α-
hydroxymethylenebisphosphonic acids from the corresponding
carboxylic acids – A mechanistic overview. Curr. Org. Chem.,
2017, 21, 1567-1578.
Keglevich, G.; Grün, A.; Aradi, K.; Garadnay, S.; Greiner, I.
Optimized synthesis of N-heterocyclic dronic acids; closing a
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Kieczykowski, G. R.; Jobson, R. B.; Melillo, D. G.; Reinhold, D.
F.; Grenda, V. J.; Shinkai, I. Preparation of (4-amino-1-
hydroxybuty1idene)bisphosphonic acid sodium salt, MK-217
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CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
[13]
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Bhimavarapu, S. R.; Bolugoddu, V. B.; Donthula, A.; Elati, C. S.
R. R.; Sait, S.; Tondepu, N.; Vakamudi, V. P. S. N. Preparation of
risedronate sodium hemi-pentahydrate. WO2009/3001, 2008.
Grün, A.; Kovács, R.; Garadnay, S.; Greiner, I.; Keglevich, G. The
synthesis of risedronic acid and alendronate applying phosphorus
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ACKNOWLEDGEMENTS
The research was supported by Gedeon Richter Plc and
by the National Research, Development and Innovation Of-
fice (K119202).
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