Efficient synthesis of pamidronic acid using an ionic liquid additive

Article abstract of DOI:10.2174/1570180812666151022221805

An efficient method was developed for the synthesis of pamidronic acid involving the reaction of β-alanine with three equivalents of phosphorus trichloride and two equivalents of phosphorous acid at 75 °C in the presence of 0.3 or 0.6 equivalents of [BMIM][PF₆] as an additive.

Full text of DOI:10.2174/1570180812666151022221805

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Letters in Drug Design & Discovery, 2016, 13, 475-478
eISSN: 1 58 7 05 - 16 82 08 8X
Volume 13, Number 6
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Efficient Synthesis of Pamidronic Acid Using an Ionic
Liquid Additive
SB EC N
I
ET NH AC ME
1
1
2
2
1,*
Alajos Grün , Dávid Illés Nagy , Sándor Garadnay , István Greiner and György Keglevich
1
Department of Organic Chemistry and Technology, Budapest University of
2
Technology and Economics, 1521 Budapest, Hungary; Gedeon Richter Plc.,
1
475 Budapest, Hungary
Abstract: An efficient method was developed for the synthesis of pamidronic acid
involving the reaction of ꢀ-alanine with three equivalents of phosphorus trichloride
and two equivalents of phosphorous acid at 75 °C in the presence of 0.3 or 0.6 equiva-
6
lents of [BMIM][PF ] as an additive.
Keywords: Pamidronic acid, best synthesis, additive, ionic liquids, interme-
diate.
István Greiner
Received: September 08, 2015
Revised: October 16, 2015
Accepted: October 22, 2015
1
. INTRODUCTION
-Hydroxy-1,1-bisphosphonic acid derivatives are of im-
75 °C using sulfolane and MSA as the solvent, respectively.
The optimum molar ratio of phosphorus trichloride and
phosphorous acid was 2:2 in sulfolane, and 3.2:0 in MSA.
The optimized syntheses resulted in the formation pure pa-
midronic acid and sodium pamidronate in a yield of 63% and
1
portance due to their activity against bone diseases, like os-
teoporosis, hypercalcemia, osteolyc metastases and the
Paget’s disease [1-5]. The 1-hydroxy geminal bisphosphonic
acids have a tridentate functionality to enable the binding of
Ca ions, and to promote the affinity for species responsible
for the accumulation of phosphates in the bone tissues [1-9].
5
7%, respectively [16]. We suggested a novel mechanism for
2
+
the formation of pamidronic acid, which was based on the
optimum molar ratio of the P-reactants. Hence, in sulfolane,
(
HO)
2
P-O-PCl-O-P(OH)
2
or (HO)
P-O-SO
2
2
P-O-PCl
2
may be the
The pamidronic acid is a second generation hydroxy-
methylenebisphosphonic acid that was synthetized from ꢀ-
alanine in various solvents (e.g. sulfolane, chlorobenzene,
methanesulfonic acid (MSA) etc.), using, in most cases,
phosphorus trichloride and/or phosphorous acid as the P-
reagent, but phosphorus oxychloride was applied as well.
The reaction temperature changed between 65–130 °C, while
the reaction time fell in the range of 1-20 hours.
P-nucleophile, while in MSA, Cl
2
Me may be the
active species reacting with the first acid chloride or
anhydride type intermediates [16].
To date, just De Ferra and co-workers have employed
ionic liquid (IL) (Bu N•HCl) as the solvent in the synthesis
3
of pamidronate. ꢀ-Alanine was reacted with 2 equivalents of
phosphorus trichloride and 1 equivalent of phosphorous acid
at 65 °C for 2 h. The pure dronate was obtained in a low
yield (26%) [17].
As the first case, ꢀ-alanine was reacted with 1.5 equiva-
lents of phosphorus trichloride and the same amount of
phosphorous acid at 132 °C in chlorobenzene, and the pure
dronic acid was obtained in a yield of 59% [10]. Pamidronic
acid was synthesized applying phosphorus trichloride and
phosphorous acid in a molar ratio of 2:1.5 without any sol-
vent. The yield was 61% [11]. Monosodium pamidronate
was prepared in a yield of 60% from ꢀ-alanine using 2
equivalents of phosphorus trichloride and 1.5 equivalents of
phosphorous acid at 70–75 °C in acetonitrile [12]. The
synthesis was also carried out in MSA, and the yield was
In most cases, MSA was used as the solvent in the
synthesis of dronic acid derivatives. However, it is not a
green solvent, and during the pH adjustment, it reacts with
NaOH, and generates sodium mesylate, which is difficult to
remove. The sulfolane is also a problematic solvent due
to its price and disadvantageous properties (viscosity,
hygroscopicity and melting point). ILs are regarded to be
green solvents, and have low vapor pressure, high thermal
stability, and can be recycled or reused. However, ILs were
described only in one instance as the solvent in the synthesis
of dronic acid derivatives [17]. It was a challenge for us to
evaluate the role of ILs in the synthesis of pamidronic acid
that is a suitable model. It is also an option to apply the
ILs in a smaller quantity as a catalyst or as an additive. A
number of examples are known, where ILs have been used as
efficient catalysts [18-20].
5
7% [13-14]. The best yield (72%), was achieved by apply-
ing 3 equivalents of phosphorus trichloride and 3 equivalents
of phosphorous acid at 65 °C in sulfolane [15]. Carrying out
the reaction under microwave conditions at 65 °C for 3 min,
McKenna et al. obtained sodium pamidronate in a yield of
6
4% [15].
In our earlier work, we studied the formation of pa-
midronic acid and sodium pamidronate from ꢀ-alanine at
2
. RESULTS AND DISCUSSION
The preparation of pamidronic acid (2) and its salt from
-alanine (1) and P-reagents was found to be a good model
*
Address correspondence to this author at Department of Organic Chemis-
try and Technology, Budapest University of Technology and Economics,
521 Budapest, Hungary; Tel: 36-1-463-1111/5883;
Fax: 36-1-463-3648; E-mail: gkeglevich@mail.bme.hu
ꢀ
reaction in our earlier studies [16]. For this, we decided to
choose this model to investigate the possibility of applying
1
1
875-628X/16 $58.00+.00
©2016 Bentham Science Publishers

4
76 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Grün et al.
Table 1. Preparation of Pamidronic Acid (2) Using Phosphorus
Trichloride (2 equivalents) and Phosphorous Acid (2
Table 2. Synthesis of Pamidronic Acid (2) from ꢀ-Alanine (1)
in the Presence of
3 mL (0.6 equivalents) of
equivalents) in Different Amounts of [BMIM][PF
the Solvent.
6
] as
6
[BMIM][PF ] Using Phosphorus Trichloride and
Phosphorous Acid in Different Ratios.
Amount of [BMIM][PF
6
]
Reactants
Purity (%)
a,b
b
a,b
b
Entry
Purity (%)
Yield of 2
Entry
Yield of 2
mL
equiv.
PCl
3
(equiv.)
H
3
PO
3
(equiv.)
1
2
3
4
5
10
3
2
>99
>99
42
70
71
65
64
44
61
1
2
3
4
5
6
7
8
0
1
1
2
2
3
3
3
3
1
2
1
2
0
1
2
-
0
0.6
0.3
0.2
0.1
0
>99
>99
>99
>99
-
41
37
49
70
0
1.5
1
>99
>99
0.5
0
>99
6
>99
c
7
[11]
0
0
no data
>99
>99
41
72
a
On the basis of potentiometric titration.
From at least two parallel experiments.
Using 2 equivalents of phosphorus trichloride and 1.5 equivalents of phosphorous
acid.
b
e
a
On the basis of potentiometric titration.
From at least two parallel experiments.
b
1
) 75 °C/3 h
O
6
[BMIM][PF ], we sought to find the best quantity and molar
PCl and/or H PO
3
3
3
HO
[
BMIM][PF ]
ratio of phosphorus trichloride and phosphorous acid. The
results obtained in the presence of 3 mL (0.6 equivalents) of
6
P
OH
OH
H N
2
O
H N
2
[
6
BMIM][PF ] are listed in Table 2. It can be seen that using
OH
2) 105 °C/1 h
HO
P
phosphorus trichloride or phosphorous acid alone, there was
no formation of pamidronic acid (Table 2/Entries 1 and 6).
Applying phosphorus trichloride and phosphorous acid in a
ratio of 1:1, 1:2, 2:1 and 2:2, the yields of the target dronic
acid (2) were 41%, 37%, 49% and 70%, respectively (Table
H O
1
2
OH
3) 0-5 °C, 3 h
O
2
Scheme (1).
2
/Entries 2-5). The use of 3 equivalents of phosphorus
ionic liquids as solvent, or only as additive in the synthesis
of dronic acid derivatives. Phosphorus trichloride and phos-
phorous acid were applied in different ratios as the P-
reactants. In the first approach, 1-butyl-3-methylimidazolium
trichloride together with 1 or 2 equivalent(s) of phosphorous
acid led to a yield of 41% and 72%, respectively (Table
2/Entries 7 and 8). In all cases, pure pamidronic acid was
formed according to the titrations. One may conclude that
the molar ratios of 2:2 and 3:2 are the most advantageous in
respect of phosphorus trichloride and phosphorous acid. In
these cases, the yields exceeded 70%.
6
hexafluorophosphate ([BMIM][PF ]) was chosen as the ionic
liquid to be tested. Heating at 75 °C for 3 h on intensive stir-
ring was followed by hydrolysis at 105 °C for 1 h. Then,
pamidronic acid (2) precipitated on cooling. The purification
involved digestion in methanol (Scheme 1).
The next series of experiments was carried out in the
presence of 1.5 mL (0.3 equivalents) of [BMIM][PF ]. The
6
First, the effect of the quantity of the IL chosen was
evaluated. The results are summarized in Table 1. It was
found that decreasing the quantity of the IL from 10 mL to 3
mL, 1.5 mL, 1 mL, 0.5 mL and finally to 0 mL, the yields of
pamidronic acid followed a function going through maxi-
mum, and were 42%, 70%, 71%, 65%, 64% and 44%, re-
spectively (Table 1/Entries 1-6). In the absence of any sol-
vent using 2 equivalents of phosphorus trichloride and 1.5
equivalents phosphorous acid at 100 °C for 4 h, the yield
reported was 61%, however, no data on the purity was pro-
vided [11]. It can be concluded that it is not advisable to use
tendency was exactly the same that was observed using
twice as much IL (Table 3). The best results (70/71% yield)
were obtained using phosphorus trichloride and phosphorous
acid in a ratio of 2:2 and 3:2 (Table 3/Entries 4 and 6).
The reacting species that was added to the C=O group of
-alanine is obviously Cl P-O-P(OH) .
2 2
ꢀ
6
It can be concluded that it is enough to use [BMIM][PF ]
as an additive in a quantity of 0.3 or 0.6 equivalents, and the
best is, when phosphorus trichloride and phosphorous acid
are applied in a ratio of 2:2 or 3:2. The novel method af-
forded pamidronic acid in better yields, than the earlier pro-
cedures [16].
[
6
BMIM][PF ] as the solvent. The application of a quantity of
only 0.6 or 0.3 equivalents is more appropriate. Hence, it is
better to measure in the IL as an additive and not as the sol-
vent.
Although the use of 0.3 or 0.6 equivalents of
[
6
BMIM][PF ] was rather efficient both at a 2:2 or 3:2 molar
ratio of phosphorus trichloride and phosphorous acid, we
wished to try out a few other ILs such as, 1-butyl-3-
Accepting the “message” of the previous experiments
that it is better to use only 0.3 or 0.6 equivalents of

Efficient Synthesis of Pamidronic Acid Using an Ionic Liquid Additive
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6 477
Table 3. Synthesis of Pamidronic Acid (2) from ꢀ-Alanine (1)
3. SUMMARY
in the Presence of 1.5 mL (0.3 equivalents) of
It was found that the synthesis of pamidronic acid from ꢀ-
alanine and P-reagents, like phosphorus trichloride and
phosphorous acid may be advantageously carried out in the
[
6
BMIM][PF ] Using Phosphorus Trichloride and
Phosphorous Acid in Different Ratios.
6
presence of [BMIM][PF ] as an additive. Hence, using the
Reactants
above components in a molar ratio of 1:2:2:0.3, after a reac-
tion at 75 °C for 3 h, the product was obtained in a yield of
a
b
Entry
Purity (%)
Yield of 2
PCl
3
(equiv.)
H
3
PO
3
(equiv.)
7
1%.
1
2
3
4
5
6
1
1
2
2
3
3
1
2
1
2
1
2
>99
>99
>99
>99
>99
>99
42
35
47
71
41
70
4
4
. EXPERIMENTAL
.1. General
3
1
P NMR spectra were obtained on a Bruker AV-300
spectrometer at 121.50 MHz; chemical shifts were downfield
3 4
relative to 85% H PO . The pamidronic acid content of the
samples was determined by potentiometric acid-base titra-
tions on a Mettler DL77 potentiometric titrator.
a
On the basis of potentiometric titration.
From at least two parallel experiments.
b
The titration curve for pure pamidronic acid (2) synthe-
sized by us (Table 2/Entry 8) is shown in Fig. (1).
methylimidazolium chloride ([BMIM][Cl]), 1-butyl-3-
methylimidazolium tetrafluoroborate ([BMIM][BF
ethyl-3-methylimidazolium ethanesulfonate
EtSO ]). The results are summarized in Table 4. For com-
4
]), and 1-
([EMIM]
4
.2. Typical Procedure for the Preparation of Pamidronic
Acid (2) from ꢀ-Alanine (1), Phosphorous Trichloride
and Phosphorous Acid in the Presence of [BMIM][PF
Table 2/Entry 8)
[
3
6
]
parison purposes, the relevant results obtained with the use
of [BMIM][PF ] are also included.
(
6
2
.2 g (0.025 mol) of ꢀ-Alanine (1) and 4.3 g (0.053 mol)
It can be seen that the yields of dronic acid 2 were lower
in all cases applying ILs other than [BMIM][PF ]. Using 0.3
equivalents of [BMIM][BF ] and [BMIM][Cl] together with
a molar ratio of 3:2 of phosphorus trichloride and phospho-
rous acid, the yield of product 2 was 61% and 33%, respec-
tively (Table 4/Entries 2 and 3), as compared to the outcome
phosphorous acid were added into 3 mL (0.015 mol) of 1-
butyl-3-methylimidazolium hexafluorophosphate on stirring.
Then, 7 mL (0.080 mol) of phosphorous trichloride was
added dropwise in ca. 30 min, and the contents of the flask
were stirred at 75 °C for 3 h. After cooling the mixture to
6
4
2
6 °C, 10 mL (0.53 mol) of water was added and the mixture
of 70% obtained with [BMIM][PF
6
] under similar conditions
was stirred further at 105 °C for 1 h. Then, the mixture was
stirred at 26 °C for 12 h, and finally at 0-5 °C for 3 h. The
precipitate was removed by filtration to give ~5 g of the
crude product that was suspended in 15 mL of methanol, and
the mixture was digested by stirring at 65 °C for 30 min. The
solid product was filtered off to furnish 4.2 g (72%) of pa-
(
[
Table 4/Entry 1). Similarly, measuring [BMIM][Cl] or
3
EMIM][EtSO ], and applying the P-reagents in a 2:2 molar
ratio, the yield of dronic acid 2 was 40% and 48%, respec-
tively, that is lower than the yield of 70% obtained with
[
[
BMIM][PF
BMIM][PF
6
] (Table 4/Entries 4-6). As can be seen, indeed,
] is the best choice for an IL to be used as cata-
3
1
6
midronic acid (2) in a purity of >99%. P NMR (D O) ꢀ:
2
17.6, ꢀ [16]: 17.6; 13C NMR (D
O) ꢀ: 72.8 (t, J = 132.8,
2
lyst in our model reaction.
Table 4. The Effect of Different ILs on the Synthesis of Pamidronic Acid (2) from ꢀ-Alanine (1) Using Phosphorus Trichloride and
Phosphorous Acid.
Reactants
a
b
Entry
Type of IL
Quantity of IL
Purity (%)
Yield of 2
PCl
3
(equiv.)
H
3
PO
3
(equiv.)
1
2
3
4
5
6
[BMIM][PF
6
]
0.3
0.3
0.3
0.6
0.3
0.6
3
3
3
2
2
2
2
2
2
2
2
2
>99
>99
>99
>99
>99
>99
70
61
33
70
40
48
[BMIM][BF
4
]
[BMIM][Cl]
[BMIM][PF
6
]
[BMIM][Cl]
[EMIM][EtSO ]
3
a
On the basis of potentiometric titration.
b
From at least two parallel experiments.

4
78 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Grün et al.
300
200
100
0
O
HO
O
HO
P
OH
P ONa
OH
H
2
N
2
H N
OH
P
OH
P
HO
O
OH
-
-
-
100
200
300
HO
O
O
HO
O
ONa
OH
HO
P
ONa
OH
P
H
2
N
2
H N
HO P OH
O
HO P ONa
O
0
1
2
3
4
5
6
7
8
9
10
Volume [mI]
Fig. (1). Titration curve for pure pamidronic acid (2) obtained by the reaction presented in Table 2/Entry 8.
[
8]
9]
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PCP), 36.5 (t, J = 7.5, NCH
5.3 (t, J = 133.0, PCP), 39.0 (t, J = 7.7, NCH
NCH ).
2
CH
2
), 30.8 (s, NCH
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[
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CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
5
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Zhibo, Q.; Xiaolan, C.; Chen, Q.; Lingbo, Q.; Jinwei, Y.; Donghui,
W.; Huina, L.; Xiaoying, H.; Yuqin, J.; Yufen, Z. Fragmentation
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The research was supported by Gedeon Richter Plc and
by Hungarian Scientific and Research Fund (OTKA K83118
and K115421).
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