NAGY et Al.
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trichloride was added dropwise in ca. 30 min, and the contents
of the flask were stirred at 75°C for 3 hour. After cooling the
mixture to 25°C, 22 mL (1.2 mol) of water was added, and
the mixture was stirred further at 105°C for 3 hour. Next, the
mixture was cooled to 25°C, and the pH was adjusted to 4.3
by adding ~4 mL of 50% aqueous sodium hydroxide. The stir-
ring was continued for 12 hour, the precipitate was removed
by filtration, and dried to give 6.0 g of the crude product. The
solid was taken up in fourfold amount (24 mL) of hot water,
and the solution stirred at 25°C for 12 hour. Finally, the solid
was filtered off, and dried to furnish 4.3 g (52%) of monoso-
dium alendronate trihydrate (2) in a purity of 99%. 31P NMR
(D2O) δ: 17.9, δ[9]: 18.0, δ[12]: 18.6; 1H NMR (D2O) δ: 1.77-
1.50 (m, 4H, NCH2CH2CH2), 2.42 (t, J=6.9, 2H, NCH2),
δ[38]: 2.0-1.96 (m, 4H), 3.06-3.04 (t, 2H); 13C NMR (D2O) δ:
22.3 (t, J=6.7, NCH2CH2), 30.7 (s, NCH2CH2CH2), 40.3 (t,
J=4.4, NCH2), 73.6 (t, J=134.7, PCP), δ[12]: 22.8 (t, J=6.9),
31.1 (s), 40.4 (s), 73.9 (t, J=127.6).
REFERENCES
[1] R. G. G. Russell, Bone 2011, 49, 2.
[2] R. G. G. Russell, Pediatrics 2007, 119, 150.
[3] F. H. Ebetino, A. L. Hogan, S. Sun, M. K. Tsoumpra, X. Duan,
J. T. Triffitt, A. A. Kwaasi, J. E. Dunford, B. L. Barnett, U.
Oppermann, Bone 2011, 49, 20.
[4] C. M. Szabo, Y. Matsumura, S. Fukura, M. B. Martin, J. M.
Sanders, S. Sengupta, J. A. Cieslak, T. C. Loftus, C. R. Lea, H. J.
Lee, A. Koohang, R. M. Coates, H. Sagami, E. Oldfield, J. Med.
Chem. 2002, 45, 2185.
[5] M. J. Rogers, S. Gordon, H. L. Benford, F. P. Coxon, S. P.
Luckman, J. Monkkonen, J. C. Frith, Cancer 2000, 88, 2961.
[6] A. S. Massey, S. Pentlavalli, R. Cunningham, C. M. McCrudden,
E. M. McErlean, P. Redpath, A. A. Ali, S. Annett, J. W. McBride,
J. McCaffrey, T. Robson, M. E. Migaud, H. O. McCarthy, Mol.
Pharm. 2016, 13, 1217.
[7] H. R. Hudson, N. J. Wardle, S. W. A. Blight, I. Greiner, A. Grün,
G. Keglevich, Mini Rev. Med. Chem. 2012, 12, 313.
[8] W. K. Sietsema, F. H. Ebetino, A. M. Salvagno, J. A. Bevan,
Drugs Exp. Clin. Res. 1989, 15, 389.
[9] R. Kovács, A. Grün, S. Garadnay, I. Greiner, G. Keglevich, Curr.
Org. Synth. 2013, 10, 640.
4.4
Preparation of monosodium
|
[10] G. R. Kieczykowski, R. B. Jobson, D. G. Melillo, D. F. Reinhold,
V. J. Grenda, I. Shinkai, J. Org. Chem. 1995, 60, 8310.
[11] G. R. Kieczykowski, R. B. Jobson, D. G. Melillo, US4922007,
1990, Chem. Abstr. 1990, 113, 132508.
alendronate trihydrate (2) from GABA (1),
phosphorus trichloride, and phosphorous
acid in sulfolane with IL additive (A) or in the
presence of IL (B) (Table 4, entry 2, Table 6,
entry 4)
[12] A. Grün, R. Kovács, S. Garadnay, I. Greiner, G. Keglevich, Lett.
Drug Des. Discov. 2015, 12, 253.
[13] M. I. Kabachnik, T. Y. Medved, N. M. Dyaglova, Y. M. Polikarpov,
B. K. Shcherbakov, F. I. Bel’skii, B Acad. Sci. USSR Ch. 1978, 27,
374.
A quantity of 2.6 g (0.025 mol) of GABA (1) and 4.3 g
(0.053 mol) of phosphorous acid was added into a mixture
of 8 mL of sulfolane and 1.4 mL (0.008 mol) of [bmim][BF4]
(A), or into 1.4 mL (0.008 mol) of [bmim][BF4] (B) on stir-
ring. Then, 7 mL (0.08 mol) of phosphorus trichloride was
added dropwise in ca. 30 min, and the contents of the flask
were stirred at 75°C for 3 hour. After cooling the mixture to
25°C, 10 mL (0.5 mol) of water was added, and the mixture
was stirred further at 105°C for 3 hour. Next, the mixture was
cooled to 25°C, and the pH was adjusted to 4.6 by adding
~4 mL of 50% aqueous sodium hydroxide. Then, the contents
of the flask were stirred at the same temperature for 12 hour
and finally at 0-5°C for 2 hour. Further work-up including
filtration of the crude product, and purification by recrys-
tallization from water was performed as described above to
afford 6.5 g (80%, (A), Table 4, entry 2), 5.5 g (66%, (B),
Table 6, entry 4) of monosodium alendronate trihydrate (2)
in a purity of 100% and 98%, respectively. 31P NMR (D2O)
δ: 17.9 for the product obtained from the experiment marked
by Table 4, entry 2, δ[9]: 18.0, δ[12]: 18.6.
[14] L. Widler, K. A. Jaeggi, M. Glatt, K. Müller, R. Bachmann, M.
Bisping, A. R. Born, R. Cortesi, G. Guiglia, H. Jeker, R. Klein, U.
Ramseier, J. Schmid, G. Schreiber, Y. Seltenmeyer, J. R. Green, J.
Med. Chem. 2002, 45, 3721.
[15] H. Blum, K. H. Worms, DE2534391, 1977, Chem. Abstr. 1977,
87, 68491.
[16] V. G. Gore, V. K. Shukla, M. M. Ghadge, R. M. Avadhut,
US2009/198062, 2009, Chem. Abstr. 2008, 148, 100730.
[17] S. C. Pandey, H. Haider, S. Saxena, M. K. Singh, R. K. Thaper,
S. K. Dubey, WO2006/134603, 2006, Chem. Abstr. 2006, 146,
62922.
[18] S. C. Pandey, H. Haider, S. Saxena, M. K. Singh, R. K. Thaper,
S. K. Dubey, US2009/312551, 2009, Chem. Abstr. 2006, 146,
62922.
[19] S. R. Danda, N. K. A. S. S. Garimella, S. R. V. N. Divvela, R.
Dandala, S. Meenakshisunderam, US2007/173645, 2007, Chem.
Abstr. 2007, 147, 189284.
[20] D. V. N. S. Rao, R. Dandala, G. K. A. S. S. Narayanan, R. Lenin,
M. Sivakumaran, A. Naidu, Synth. Commun. 2007, 37, 4359.
[21] U. P. Senthilkumar, T. Arulmoli, V. S. Lakshmipathi, S. M. Rao,
US2007/66569, 2007, Chem. Abstr. 2007, 146, 296069.
[22] D. V. Yanvarev, A. N. Korovina, N. N. Usanov, S. N. Kochetkov,
Russ. J. Bioorg. Chem. 2012, 38, 224.
ACKNOWLEDGMENTS
[23] P. B. Deshpande, P. K. Luthra, US2006/258625, 2006, Chem.
Abstr. 2006, 145, 511840.
The research was supported by Gedeon Richter Plc and by
the Hungarian Research Development and Innovation Fund
(K119202). We thank Orsolya Németh for participating in
the synthetic work.
[24] X. Chen, X. Huang, Y. Jiang, H. Li, L. Qu, Z. Qu, D. Wei, Y.
Zhao, C. Qu, L. Qu, J. Yuan, Y. Zhao, Int. J. Mass Spectrom.
2010, 295, 85.