€
A. GRUN ET AL.
2
Table 1. Yields and purities of dronic acid derivatives in sulfolane, or in the presence of an IL additive, or using both agents.
P-reagents (equiv.)
Dronic derivatives
Solvent or additive
Sulfolane
.1 equiv. [bmim][BF
Sulfolane
.6 equiv. [bmim][BF
PCl
3
H
3
PO
3
Purity (%)
Yield (%)
Ibandronate (4a)
3
3
2
2
2
2
2
2
2
2
2
2
2
2
100
99
100
99
99
100
100
83
90
74
75
93
58
66
0
4
]
]
Zoledronic acid (5a)
0
4
Sulfolane þ 0.6 equiv. [bmim][BF
4
]
Risedronic acid (6a)
Sulfolane
0
4
.6 equiv. [bmim][BF ]
no need for more solvent, as no purification steps
were necessary.
[2] Hudson, H. R.; Wardle, N. J.; Bligh, S. W. A.; Greiner, I.; Grun,
A.; Keglevich, G. N-Heterocyclic Dronic Acids: Applications
and Synthesis. Mini. Rev. Med. Chem. 2012, 12, 313–325.
The most often applied P-reagents in the synthesis of
a-hydroxymethylenebisphosphonic derivatives are phos-
phorus trichloride and phosphorous acid, and the preferred
solvent is methanesulfonic acid (MSA). But MSA is not con-
sidered an environmentally friendly solvent. The synthesis of
a few dronic acid derivatives was also performed in
sulfolane, or in the presence of an IL additive, or in the
[
3] R ꢀa dai, Z.; Keglevich, G. Synthesis and Reactions of
a-Hydroxyphosphonates. Molecules. 2018, 23, 1439–1468.
[
4] Rao, K. U. M.; Sundar, C. S.; Prasad, S. S.; Rani, C. R.; Reddy,
C. S. Neat Synthesis and Anti-oxidant Activity of
[
5] Kong, D. L.; Liu, R. D.; Li, G. Z.; Zhang, P. W.; Wu, M. S. A
Rapid, Convenient, Solventless Green Approach for the
[
8]
combination of sulfolane/IL. This approach was extended
[
9]
to the synthesis of ibandronate (4a) and two representa-
[
10]
tives of the third generation agents zoledronic acid (4b)
and risedronic acid (4c)
[6] Keglevich, G.; R ꢀa dai, Z.; Kiss, N. Z. To Date the Greenest
Method for the Preparation of a-Hydroxyphosphonates from
Substituted Benzaldehydes and Dialkyl Phosphites. Green
Process. Synth. 2017, 6, 197–201.
[
11]
(Scheme 2, Table 1). The joint
use of the IL additive and sulfolane as the solvent was
synergetic affording highly valuable zoledronic acid in a
[
[
[
7] R ꢀa dai, Z.; Szeles, P.; Kiss, N. Z.; Heged u} s, L.; Windt, T.; Nagy,
V.; Keglevich, G. Green Synthesis and Cytotoxic Activity of
Dibenzyl a-Hydroxyphosphonates and a-Hydroxyphosphonic
Acids. Heteroatom Chem. 2018, e21436.
8] Nagy, D. I.; Gr u€ n, A.; Garadnay, S.; Greiner, I.; Keglevich, G.
Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives
[
11]
record yield of 93%.
Funding
The above project was supported by the National Research
Development and Innovation Fund (K119202). Z. R ꢀa dai is grateful for
the fellowship provided by Chinoin–Sanofi Pharmaceuticals and J oꢀ zsef
9] Nagy, D. I.; Gr u€ n, A.; Pavela, O.; Garadnay, S.; Greiner, I.;
Keglevich, G. Efficient Synthesis of Ibandronate in the Presence
ꢀ
Varga Foundation. Z. R ꢀa dai was supported by the UNKP-18-3-IV-
BME-265 New National Excellence Program of the Ministry of
Human Capacities.
[
10] Nagy, D. I.; Gr u€ n, A.; L ꢀe vay, K.; Garadnay, S.; Greiner, I.;
Keglevich, G. Efficient Syntheses of Zoledronic Acid as an
References
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