The synthesis of pamidronic derivatives in different solvents: An optimization and a mechanistic study

Article abstract of DOI:10.1002/hc.21155

The synthesis of pamidronic acid and sodium pamidronate dihydrate from β-alanine and P-reagents (phosphorus trichloride and phosphorous acid) was investigated at 75°C in different solvents, and the preparation was optimized. In sulfolane, the use of 2 equiv of phosphorus trichloride and phosphorous acid was found the optimum to lead to pamidronic acid in a yield of 63%. In methanesulfonic acid, 3.2 equiv of phosphorus trichloride was necessary without any phosphorous acid to give pamidronate dihydrate in the best yield (57%) after hydrolysis and pH adjustment. In the first case, the P-nucleophile may be (HO)₂P-O-PCl-O-P(OH)₂ or (HO)₂P-O- PCl₂, whereas in the second case, the P-reactant is probable Cl ₂P-O-S(O)₂Me. It can be said that the mechanism proposed for the formation of pamidronic acid is highly influenced by the solvent used, as it determines the necessary P-reagent(s). Our results promote the "on purpose" planning of the synthesis of dronates.

Full text of DOI:10.1002/hc.21155

Heteroatom Chemistry
Volume 25, Number 3, 2014
T
he Synthesis of Pamidronic Derivatives
in Different Solvents: An Optimization
and a Mechanistic Study
1
1
1
2
Rita Kov a´ cs, Alajos Gr u¨ n, Orsolya N e´ meth, S a´ ndor Garadnay,
2
1
Istv a´ n Greiner, and Gy o¨ rgy Keglevich
1
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2Gedeon Richter Plc, 1475 Budapest, Hungary
Received 10 February 2014; revised 19 March 2014
odicals, Inc. Heteroatom Chem. 25:186–193, 2014;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21155
ABSTRACT: The synthesis of pamidronic acid and
sodium pamidronate dihydrate from β-alanine and
P-reagents (phosphorus trichloride and phosphorous
acid) was investigated at 75°C in different solvents,
and the preparation was optimized. In sulfolane, the
use of 2 equiv of phosphorus trichloride and phos-
phorous acid was found the optimum to lead to
pamidronic acid in a yield of 63%. In methane-
sulfonic acid, 3.2 equiv of phosphorus trichloride
was necessary without any phosphorous acid to give
pamidronate dihydrate in the best yield (57%) after
hydrolysis and pH adjustment. In the first case, the
P-nucleophile may be (HO)2P–O–PCl–O–P(OH)2
or (HO)2P–O–PCl2, whereas in the second case,
the P-reactant is probable Cl2P–O–S(O)2Me. It can
be said that the mechanism proposed for the for-
mation of pamidronic acid is highly influenced by
the solvent used, as it determines the necessary P-
reagent(s). Our results promote the “on purpose” plan-
ning of the synthesis of dronates. ꢀC 2014 Wiley Peri-
INTRODUCTION
Carbon-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
2+
Ca ions and to promote the affinity for species
responsible for the accumulation of phosphates in
the bone tissues [1–9].
Pamidronic acid belongs to the second genera-
tion of hydroxy-methylenebisphosphonic acids. The
first synthesis of pamidronic acid was described in
1973, reacting β-alanine, 1.5 equiv of phosphorus
trichloride, and 1.5 equiv of phosphorous acid in
chlorobenzene at 132°C for 3 h. After hydrolysis
and separation of the phases, the pamidronic acid
was crystallized from the water phase in a yield of
59% [10]. Later on, the synthesis was accomplished
Correspondence to: Gy o¨ rgy Keglevich; e-mail: gkeglevich@
applying 2 equiv of phosphorus trichloride and 1.5
equiv of phosphorous acid. The reaction was car-
ried out in acetonitrile at 70–75°C for 6–9 h fol-
lowed by hydrolysis and pH adjustment to afford
monosodium pamidronate in a yield of 60% [11].
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
´
Contract grant number: OTKA No K83118 and TAMOP-4.2.1/B-
9/1/KMR-2010–0002.
2014 Wiley Periodicals, Inc.
0
ꢀ
C
186

Synthesis of Pamidronic Derivatives in Different Solvents 187
In another variation, monosodium pamidronate
was prepared in methanesulfonic acid (MSA) as
the solvent [12, 13] in a yield of 57% [12]. Using
sulfolane as the solvent and utilizing microwave
irradiation, McKenna et al. obtained monosodium
pamidronate in a yield of 64% whereas under con-
ventional thermal conditions the yield was 72% [14].
When pamidronic acid was the target, β-alanine,
phosphorus trichloride, and phosphorous acid were
reacted as shown above [10], or the components
were measured in a molar ratio of 1:3.4:1.5 apply-
ing sulfolane as the solvent. After heating the com-
ponents at 63–67°C for 3 h followed by hydrolysis
at 0→100°C and cooling the reaction mixture to
P-reagents using sulfolane or MSA as the solvent.
We were also interested in exploring further mecha-
nistic details [24].
RESULTS AND DISCUSSION
The Synthesis of Pamidronate in Sulfolane
First, we wished to study the preparation of
pamidronic acid (1) from β-alanine, phosphorus
trichloride, and phosphorous acid using sulfolane as
the solvent in details. The synthesis was carried out
at 75°C for 12 h applying the P-reagents in different
ratios. The reaction was followed by hydrolysis and
crystallization (Scheme 1). Experimental data are
listed in Table 1. When phosphorous acid or phos-
phorus trichloride was used alone in a quantity of
0–5°C, the dronic acid was obtained in a yield of 63%
and with a purity of 99% in a crystalline form [15].
In another variation, diphenyl ether was suggested
as the solvent, but no preparative details were pro-
vided [16]. It is also possible to convert pamidronic
acid to the disodium salt by treating with 2 equiv of
sodium hydroxide [17].
In the literature, there are a variety of procedures
for the preparation of dronic acids/dronates start-
ing from the corresponding carboxylic acids and the
P-reagents, such as phosphorus trichloride and
phosphorous acid. However, the reactions were
never optimized in respect of the ratio of the re-
actants and other reaction conditions. We tried to
study the “black-box” of the synthesis of dronates
by systematic investigations. It was shown via the
example of risedronate [18, 19], zoledronate [18,
3.2 equiv, no pamidronate was formed (Table 1, en-
tries 1 and 7). Applying phosphorus trichloride and
phosphorous acid in ratios of 1:2 and 2:1, the yield
was 44% and 42%, respectively (Table 1, entries 2
and 3). The outcome was the best, when phosphorus
trichloride and phosphorous acid were measured in
a ratio of 2:2. In this instance, the yield of dronic
acid 1 was 63% (Table 1, entry 4). Modifying the 2:2
ratio to 3.2:2, the yield of compound 1 dropped to
5
5% (Table 1, entry 5), while a ratio of 3.2:1 led to
even a lower yield of 34% (Table 1, entry 6). In all
cases, completely pure or almost entirely pure (99%)
product was obtained.
1
9], ibandronate [20], alendronate [20], etidronate
O
1
) 75°C/12 h
HO
[21], and fenidronate [22] that if MSA is the sol-
PCl and/or H PO
3
3
3
P
OH
OH
vent, 3.2 equiv of phosphorus trichloride should
be used as the P-reagent without any phosphorous
acid.
H N
O
sulfolane
H N
2
2
2) 105°C/3 h
OH
HO P
H O
2
OH
O
1
Not much is known about the mechanism of
the reaction of carboxylic acids with P-reagents to
afford dronic acids/dronates. However, there are
interesting hints and ideas given by Lecouvey and
Leroux on mechanistic aspects [23]. They also pro-
posed that the first intermediate may be the acid
chloride formed from the carboxylic acid by a reac-
tion with phosphorus trichloride. This was proved by
us experimentally [24]. It was a valuable observation
of the French authors that phosphorous acid does
not react with the carboxylic acid in itself, only if it
was “partially replaced” by phosphorus trichloride.
However, the exact and optimum ratio was not pro-
posed and no explanation was given how the reaction
takes place. The role of different solvents should also
be considered. It can be said that not less important
questions remained unanswered.
3) 0–5°C, 4 h
SCHEME 1
TABLE 1 Synthesis of Pamidronic Acid (1) from β-Alanine
in Sulfolane Using Phosphorus Trichloride and Phosphorous
Acid in Different Ratios
Reactants
PCl
(equiv)
3
H
3
PO
3
Puritya
(%)
Yield of 1a,b
Entry
(equiv)
(%)
1
2
3
4
5
6
7
0
1
2
2
3.2
3.2
3.2
3.2
2
1
2
2
1
0
0
99
99
100
100
99
0
44
42
63
55
34
0
–
We now wished to study the preparation of
pamidronic acid/pamidronate from β-alanine and
a
On the basis of potentiometric titration.
From at least two parallel experiments.
b
Heteroatom Chemistry DOI 10.1002/hc

188 Kov a´ cs et al.
2
(HO) P + PCl3
3
−
2 HCl
(
HO) P O PCl O P(OH)2
2
H N
2
O
PCl
3
H N
2
O
3
OH
Cl
2
O
H N
2
O
H N
2
Cl
O
4
(HO) P
O
PCl O P(OH)2
2
−
Cl P O P(OH)2
2
(
HO) P
PCl O P(OH)2
2
Cl
6
5
OH
(
HO) P O PCl2
2
H N
2
OH
H N
O
6
P
H O
2
2
1
OPCl2
−
(HO) P
3
− HCl
(
HO) P
O
O
2
(
HO) P
O
2
7
8
SCHEME 2
It is quite surprising that phosphorus trichlo-
ride did not react with β-alanine in sulfolane. Us-
ing MSA as the solvent, phosphorus trichloride was
reactive [18, 20–22]. It is also noteworthy that the
best yield (63%) was achieved at the 2:2 molar ra-
tio of phosphorus trichloride and phosphorous acid.
How can it be explained? A rational explanation may
be that in the first step, β-alanine is converted to
the appropriate acid chloride (2) by reaction with
rous acid and hydrochloric acid as the by-products
(Scheme 2).
If phosphorus trichloride and phosphorous acid
are applied in a ratio of 3:2, then the 2 equiv of phos-
phorus trichloride that remains after the formation
of the acid chloride (2) may react with the 2 equiv of
phosphorous acid to give Cl2P–O–P(OH)2 (6). This
P-nucleophile may also react with acid chloride 2 to
afford adduct 9 and then intermediate 10, whose sta-
bilization leads to ketophosphonic acid 7 and phos-
phorus trichloride. Species 7 may then react with an-
other unit of (HO)2P–O–PCl2 (6) or with phosphorus
trichloride to provide dronic acid 1 after hydrolysis
of the second adduct that was not shown in detail
(Scheme 3).
1
equiv of phosphorus trichloride. The remaining
phosphorus trichloride may react with the 2 equiv
of phosphorous acid to furnish (HO)2P–O–PCl–O–
P(OH)2 (3) that may react with the acid chloride
(
2) giving adduct 4 and then intermediate 5 that
provides ketophosphonic acid 7 and Cl2P–O–P(OH)2
6). Interaction of the latter two species 6 and 7
(
Comparing the yields (55% vs. 63%), the reaction
sequence shown in Scheme 3 seems to be somewhat
less efficient than the other one shown in Scheme 2.
may lead to a second adduct 8, whose hydrolysis
may furnish pamidronic acid 1, as well as phospho-
(
HO) P + PCl
3 3
−
HCl
PCl2
O
(
HO) P
O
2
H N
2
H N
O
O
6
2
Cl
O
Cl
(HO) P
PCl2
2
2
9
(
HO) P
O
PCl2
2
H N
2
H N
O
6
H O
2
2
1
(
HO) P
O
PCl2
− PCl3
or
PCl3
2
(
HO) P
O
2
Cl
7
10
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Pamidronic Derivatives in Different Solvents 189
1
) 75°C/12 h
PCl and/or H
MeSO
) 105°C/4 h
hydrate, 11) was very low (3%) and the purity was
also insufficient (Table 2, entry 2). Increasing the
proportion of the phosphorus trichloride to 2.2 equiv
and adding 1.1 or 2.2 equiv of phosphorous acid to
the mixture, the yield of the product (11) was 28%
and 27%, respectively, with a purity of 97/96% (Ta-
ble 2, entries 3 and 4). The best results were obtained
when 3.2 equiv of the phosphorus trichloride was
used as the only reagent. In this case, the yield of
pamidronate dihydrate was 57% and the purity was
3
3 3
PO
3
H
O
HO
2
P
ONa
OH
H
2
O
2
H N
H
2
N
O
3
4
2
) 50% NaOH/H O, pH = 1,8
OH
HO P
×
2
2 H O
) purification
OH
O
11
SCHEME 4
According to a literature method [17], apply-
ing sulfolane as the solvent along with phosphorus
trichloride and phosphorous acid in a 3.4 equiv and
a 1.5 equiv quantity, respectively, the yield of pure
pamidronic acid (1) was claimed to be 63%, but no
criterion of purity was provided. Our reproduction
at the given molar ratio led to a yield of only 44%
in a pure form. The purity was supported by poten-
tiometric titration and NMR spectra. The yield of
9
9% (Table 2, entry 5).
It is a noteworthy experience that phosphorus
trichloride was not of enough reactivity in sulfolane
as the solvent; however, using MSA as the solvent,
the best results were obtained with phosphorus
trichloride alone (without phosphorous acid). It is
possible that phosphorus trichloride is more reac-
tive in the more polar solvent of MSA. It is, however,
more probable that phosphorus trichloride forms an
anhydride with MSA that can be formulated as Cl2P–
O–S(O)2Me (12). Considering also that in the first
step not only an acid chloride (2), but a mixed an-
hydride (13) may also be formed (the latter in two
ways, either via 2 or by the reaction of β-alanine
with MeSO2Cl), the reaction sequence represented
by Scheme 5 may be proposed. Then, the carbonyl
carbon of species 2 and 13 is attacked by the P
atom of mixed anhydride 12 to furnish adduct 14
44% is in accord with the fact that the molar ratio
described earlier [17] is not optimal.
The Synthesis of Pamidronate in MSA
Recalling our general method elaborated for the syn-
thesis of dronates, we wished to apply this also to
the preparation of pamidronate (11). In these experi-
ments, the solvent was MSA instead of sulfolane. The
effect of the molar ratios of phosphorus trichloride
and phosphorous acid on the outcome was investi-
gated in reactions carried out at 75°C for 12 h. The
reaction was followed by hydrolysis, pH adjustment,
digestion in MeOH, treatment by MeOH in water at
pH 5.5–6, and another digestion in MeOH (Scheme
ꢀ
ꢀ
that is stabilized by the loss of Y (that is Cl or
MeSO3 ). α-Keto intermediate 15 so formed reacts
ꢀ
then with another unit of the mixed anhydride 12
to give adduct 16, and after hydrolysis pamidronic
acid 1 that is transformed to its sodium salt dihy-
drate (11) by pH adjustment. It is also possible that
intermediate 15 is somehow stabilized before the at-
tack of a second unit of Cl2P–O–S(O)2Me (12).
In a separate experiment, MSA and 1 equiv of
phosphorus trichloride were stirred in an ethereal
4). Experimental details are listed in Table 2.
Using phosphorous acid alone, there was no re-
action (Table 2, entry 1). When 1.1 equiv of phospho-
rus trichloride was applied together with 2.2 equiv
of phosphorous acid, the yield of the monosodium
salt of pamidronic acid dihydrate (pamidronate di-
3
1
solution at 26°C. After a reaction time of 6 h,
P
NMR analysis revealed a signal at δP 178.3 (CDCl3)
that may support the structure Cl2P–O–SO2Me, and
hence its intermediacy in the above reaction. The
predicted P NMR chemical shift was δP 179.3 ± 5.4
using ACD/Chem Sketch software version 4.55/2002.
The reaction sequence shown in Scheme 5 may
be of general value, and hence may be valid for the
formation of other dronic acids as well. In this sense,
the mechanism proposed for the formation of zole-
dronate and risedronate must be refined [18].
Then, we wished to prove the first and second
step of the mechanism suggested in Scheme 5. For
this, the optimized synthesis of pamidronate dihy-
drate 11 was accomplished in two steps: reacting
β-alanine first with 1.1 equiv of phosphorus trichlo-
ride or with thionyl chloride at 26°C for 4 h, and then
TABLE 2 Synthesis of Pamidronate Dihydrate (11) from
β-Alanine in MSA Using Phosphorus Trichloride and Phos-
phorous Acid in Different Ratios
3
1
Reactants
PCl
(equiv)
3
H
3
PO
3
Puritya
(%)
Yield of
11 (%)
a,b
Entry
(equiv)
1
2
3
4
5
0
3.2
2.2
1.1
2.2
0
0
58
97
96
99
0
3
28
27
57
1.1
2.2
2.2
3.2
a
On the basis of potentiometric titration.
From at least two parallel experiments.
b
Heteroatom Chemistry DOI 10.1002/hc

190 Kov a´ cs et al.
PCl3
MSA
H N
O
2
Cl
2
Cl2P O S(O) Me
2
O
12
H N
2
H N
O
MeSO H
2
PCl3
3
Y
OH
H N
2
O
Me(O)
2
S
O
14
PCl
2
MeSO Cl
2
O
O
Y = Cl, MeSO3
MSA
S
Me
O
1
3
Cl P O S(O) Me
H N
2
2
2
Cl2P
Cl2P
O
S(O) Me
2
H N
O
2
H O
2
12
1
Me(O)2S
O
PCl2
O
O
Y
S(O) Me
2
Y
15
16
SCHEME 5
Step 1
Step 2
sion, reacting the components all at once (57% vs.
7%, Table 2, entry 5 vs. Table 3, entry 1). However,
3
1
) 75°C/12 h
PCl (2.1 equiv)
MSA
2) 105°C/4 h
3
the intermediacy of acid chloride 2 and mixed anhy-
dride 13 was confirmed by these experiments.
It should be mentioned that the optimized syn-
theses may afford pamidronic acid (1) in a yield
of 63% or sodium pamidronate dihydrate (11) in a
yield of 57%. Both products were obtained in a pure
form. In the context of literature data, our yields are
reasonable.
3 2
PCl /SOCl
1.1 equiv)
(
2
2
H O
H
2
N
O
and/or
11
MSA
13
3) 50% NaOH, pH = 1.8
OH
SCHEME 6
TABLE 3 Preparation of Pamidronate Dihydrate (11) in Two
Steps Using Different Reactants
In summary, the synthesis of pamidronic acid
and sodium pamidronate was investigated and op-
timized using sulfolane and MSA, respectively, as
the solvent at 75°C. Novel mechanisms were sug-
gested on the basis of the optimum set and molar
ratio of the P-reactants. Hence, in sulfolane, (HO)2P–
O–PCl–O–P(OH)2 or (HO) P–O–PCl may be the
Inorganic
Halide (1.1
equiv)
Reactant
(2.1 equiv)
Puritya
(%)
Yield of
11 (%)
a,b
Entry
1
2
3
4
PCl
PCl
SOCl
SOCl
3
3
2
2
PCl
PO
PCl
PO
3
3
3
3
91
96
97
0
37
4
37
0
H
3
2
2
H
3
P-nucleophile, while in MSA, Cl2P–O–S(O)2Me may
be the active species reacting further with the
first acid chloride intermediate whose presence was
proved by separate two-step syntheses. Our results
provide a better understanding of the formation of
dronates in the reaction of carboxylic acids and P-
reagents and make possible to select the optimum
conditions. This is the first case that the role of the
solvent was pointed out in the selection of the suit-
able set of the P-reagents and in the course of the
reaction.
a
On the basis of potentiometric titration.
From at least two parallel experiments.
b
with 2.1 equiv of phosphorus trichloride at 75°C for
2 h. In both steps, MSA was the solvent. The re-
action sequence is shown in Scheme 6, whereas the
experimental data are listed in Table 3.
It can be seen that using either phosphorus
trichloride or thionyl chloride in the first step and
then phosphorus trichloride in the second step,
dronate dihydrate 11 was obtained in a yield of 37%
1
(
Table 3, entries 1 and 3). Using, however, phospho-
rous acid in the second step, the yield of product
1 was only, in the best case, 4% (Table 3, entries 2
EXPERIMENTAL
General
1
and 4). It can be seen that phosphorous acid is not
nucleophilic enough to participate in the dronate-
forming reaction. It can be also concluded that the
two-step variation is less efficient than the other ver-
31P NMR spectra were obtained on a Bruker
AV-300 spectrometer at 121.50 MHz; chemical
shifts are downfield relative to 85% H3PO4. The
pamidronate content of the samples was determined
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Pamidronic Derivatives in Different Solvents 191
by potentiometric acid–base titrations on a Mettler
DL77 potentiometric titrator.
sulfolane on stirring. Then, 4.4 mL (0.050 mol) of
phosphorus trichloride was added dropwise in ca.
15 min, and the contents of the flask were stirred
at 75°C for 3 h. After cooling the mixture to 0–5°C,
22.3 mL (1.2 mol) of water was added and the mix-
ture was stirred further at 105°C for 3 h. Then, the
mixture was cooled to 0–5°C and stirred for 4 h. The
precipitation was removed by filtration. 3.7 g (63%)
of pamidronic acid (1) was obtained in a purity of
The titration curve for pure pamidronic acid
(
1) synthesized by us (Table 1, entry 4) and the
monosodium salt of pamidronic acid (11) obtained
by the reaction (Table 2, entry 5) is shown in Figs. 1
and 2, respectively.
Preparation of Pamidronic Acid (1) in Sulfolane
3
1
13
100%. P NMR (D2O) δ: 17.6, δ [25]: 16.8; C NMR
(
Table 1, Entry 4)
(
D2O) δ: 75.3 (t, J = 133.0, PCP), 39.0 (t, J = 7.7,
β-Alanine (2.2 g, 0.025 mol) and phosphorous
acid (4.1 g, 0.050 mol) were added to 8.0 mL of
NCH2CH2), 33.3 (s, NCH2), δ [25]: 72.3 (t, J = 134.8,
PCP), 36.1 (s, NCH2CH2), 31.2 (s, NCH2).
400
300
200
100
0
O
O
ONa
OH
HO
HO
OH
P
P
H
2
N
2
H N
OH
P
HO P OH
O
HO
OH
O
O
O
ONa
OH
HO
HO
-
100
ONa
P
P
2
H N
2
H N
OH
P
HO P ONa
O
HO
OH
O
-200
-300
0
1
2
3
4
5
6
7
8
9
10
Volume [mL]
FIGURE 1 Titration curve for pure pamidronic acid (1) obtained by the reaction presented in Table 1 (entry 4).
2
00
00
0
1
O
O
ONa
OH
HO
HO
ONa
P
P
H
2
N
2
H N
OH
P
HO P ONa
O
HO
OH
O
-100
-200
-300
0
1
2
3
4
5
6
7
8
9
10
Volume [mL]
FIGURE 2 Titration curve for the monosodium salt of pamidronic acid (11) obtained by the reaction presented in Table 2
entry 5).
(
Heteroatom Chemistry DOI 10.1002/hc

192 Kov a´ cs et al.
Preparation of Pamidronic Acid (1) in Sulfolane
mL, 0.030 mol) was added dropwise and the mix-
ture was stirred at 26°C for 6 h. Then, 4.6 mL (0.053
mol) of phosphorus trichloride was added dropwise
and the mixture was stirred at 75°C for 18 h. Fur-
thermore, the process includes hydrolysis and pH
adjustment that was performed as described above
to afford 13.0 g of crude product. After digestion with
MeOH carried out similarly as above, 2.8 g (37%) of
pamidronate monosodium salt (11) was obtained in
According to the Literature Method
β-Alanine (2.2 g, 0.025 mol) and phosphorous acid
(3.1 g, 0.034 mol) were added to 8.0 mL (3.4 mol)
of sulfolane on stirring. Then, 7.4 mL (0.085 mol)
of phosphorus trichloride was added dropwise in ca.
1
5 min, and the contents of the flask were stirred
at 75°C for 3 h. After cooling the mixture to 0–5°C,
2.3 mL (1.2 mol) of water was added and the clear
2
3
1
a purity of 100%. P NMR (D2O) δ: 17.7, δ [26]: 18.4.
solution was stirred further at 105°C for 3 h in the
presence of 0.5 g of activated carbon. Then, the mix-
ture was filtered and the filtrate was cooled to 0–5°C
and stirred for 4 h. The precipitation was removed
by filtration. Repeating the experiment three times,
Preparation of Pamidronate Monosodium Salt
(
11) with Thionyl Chloride and Phosphorus
Trichloride in a Two-Step Reaction (Table 3,
Entry 3)
2
.5 g (44%) of pamidronic acid (1) was obtained as
3
1
an average in a purity of 100%. P NMR (D2O) δ:
7.6, δ [25]: 16.8 [17].
β-Alanine (2.2 g, 0.025 mol) was dissolved in
1
10.5 mL of MSA on stirring. Thionyl chloride
(
2.0 mL, 0.027 mol) was added dropwise and the
Preparation of the Monosodium Salt of
Pamidronate (11) Starting from β-Alanine in a
One-Step Reaction (Table 2, Entry 5)
mixture was stirred at 26°C for 6 h. Furthermore, the
process includes the second step with phosphorus
trichloride, hydrolysis, pH adjustment, and diges-
tion with MeOH was performed as described above
to afford 2.7 g (37%) of pamidronate monosodium
β-Alanine (2.2 g, 0.025 mol) was added to 10.5 mL of
MSA on stirring. Then, 7.0 mL (0.080 mol) of phos-
phorus trichloride was added dropwise in ca. 15 min,
and the contents of the flask were stirred at 75°C
for 24 h. After cooling the mixture to 26°C, 12 mL
3
1
salt (11) in a purity of 100%. P NMR (D2O) δ: 17.7,
δ [26]: 18.4.
(
0.67 mol) of water was added and the mixture was
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stirred further at 105°C for 4 h. The pH was adjusted
to 1.8 by adding ꢁ12 mL of 50% aqueous sodium hy-
droxide to the mixture. Then, the mixture was stirred
for 2 h and the precipitate was removed by filtra-
tion. The crude product was suspended in 50 mL of
methanol and the mixture was digested by stirring
at 65°C for 30 min. Then, the solid product was sus-
pended in 18 mL of water, the pH was adjusted to
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Preparation of Pamidronate Monosodium Salt
(
11) Applying Phosphorus Trichloride in a
Two-Step Reaction (Table 3, Entry 1)
[
β-Alanine (2.2 g, 0.025 mol) was dissolved in 10.5
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