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
REFERENCES
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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.5–6.0, and 50 mL of MeOH was added. The mixture
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[
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3
1
13
drate (11). P NMR (D2O) δ: 17.7, δ [26]: 18.4,
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NCH2CH2), 34.1 (s, NCH2) δ [26]: 73.1, 36.6, 31.3. TG
and DTG thermal examinations revealed the loss of
one molecule of water in the range of 162–228°C and
the loss of the other molecule of water in the range
of 228–282°C in a two-step process.
2
4(Suppl.), 73S–79S.
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2
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
mL of MSA on stirring. Phosphorus trichloride (2.6
Heteroatom Chemistry DOI 10.1002/hc