Optimized Synthesis of Etidronate
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 8 737
[8]
[9]
Russell, R.G.G.; Rogers, M.J.; Bisphosphonates: From the
laboratory to the clinic and back again. Bone, 1999, 25, 97-106.
Roelofs, A.J.; Thompson, K.; Gordon, S.; Rogers, M.J. Molecular
mechanism of action of bisphosphonates: Current status. Clin.
Cancer Res., 2006, 12, 6222-6230.
4.5. Preparation of Etidronate Disodium Salt (1) in a
Two-Step Reaction Using Phosphorus Trichloride and
then triphosgene (Table 2/Entry 4)
1.4 mL (0.025 mol) of acetic acid was dissolved in 10.5
mL of methanesulfonic acid on stirring. 2.6 g (0.026 mol) of
triphosgene was added and the mixture was stirred at 85°C
for 6 h. Further processment including the second step, hy-
drolysis, pH adjustment and precipitation with MeOH was
performed as described above, 2.7 g (43%) of Etidronate
[10]
[11]
v. Baeyer, H.; Hofmann, K.A. Acetodiphosphorige Säure. Chem.
Ber., 1897, 30, 1973-1978.
Pandey, S.C.; Haider, H.; Saxena, S.; Singh, M.K.; Thaper, R.K.;
Dubey S.K. Process for producing bisphosphonic acids and forms
thereof. WO2006134603, 2006; Chem. Abstr., 2007, 146, 62922.
Alfer'ev, I.S.; Bobkov, S.Y.; Kotlyarevskii I.L. 1-
Alkoxy(aryloxy)alkylidene-1,1-diphosphonic acids. Bull. Acad.
Sci. USSR Div. Chem. Sci., 1987, 36, 571-576.
[12]
disodium salt was obtained in a dronate content of 100%. 31
P
[13]
[14]
Schdlike, U. Phosphonylation by tetraphosphorus hexoxide.
Phosphorus, Sulfur, Silicon, 1990, 51, 153-156.
Lecouvey, M.; Mallard, I.; Bailly, T.; Burgada, R.; Leroux, Y. A
mild and efficient one-pot synthesis of 1-hydroxymethylene-1,1-
bisphosphonic acids. Preparation of new tripod ligands.
Tetrahedron Lett., 2001, 42, 8475-8478.
Nicholson, D.A.; Vaughn, H. A general method of preparation of
tetramethyl alkyl-1-hydroxy-1,l-diphosphonates. J. Org. Chem.,
1971, 36, 3843-3845.
Grün, A.; Molnár, I.G.; Bertók, B.; Greiner, I.; Keglevich G.
Synthesis of α-hydroxy-methylenebisphosphonates by the
microwave-assisted reaction of α-oxophosphonates and dialkyl
phosphites under solventless conditions. Heteroatom Chem., 2009,
20, 350-354.
NMR (D2O) δ 19.3, δ [22] 19.9 for the acid.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flicts of interest.
[15]
[16]
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[17]
Keglevich, G.; Grün, A.; Molnár, I.G.; Greiner, I. Phenyl-, benzyl-
and unsymmetrical hydroxy-methylenebisphosphonates as dronic
acid ester analogues from α-oxophosphonates by microwave-
assisted synthesis. Heteroatom Chem., 2011, 22, 640-648.
Keglevich, G.; Grün, A.; Aradi, K.; Garadnay, S.; Greiner, I.
Optimized synthesis of N-heterocyclic dronic acids; closing a
black-box era. Tetrahedron Lett., 2011, 52, 2744-2746.
Garadnay, S.; Grün, A.; Keglevich, G.; Neu, J. Novel process for
the preparation of dronic acid. WO2012107787; Chem. Abstr.,
2012, 157, 356874.
Keglevich, G.; Grün, A.; Kovács, R.; Garadnay, S.; Greiner, I.
Rational synthesis of Ibandronate and Alendronate. Curr. Org.
Synth., 2013, in press.
Keglevich, G.; Grün, A.; Kovács, R.; Koós, K.; Szolnoki, B.;
Garadnay, S.; Neu, J.; Drahos, L.; Greiner, I. Heteroarylacetyl
chlorides and mixed anhydrides as intermediates in the synthesis of
heterocyclic dronic acids. Lett. Drug Des. Discov., 2012, 9, 345-
351.
[1]
Russell, R.G.G. Bisphosphonates: The first 40 years. Bone, 2011,
49, 2-19.
Breuer, E. The development of bisphosphonates as drugs, In
Analogue-based drug discovery; Fischer, J.; Ganelli, C.R. (Eds.),
Wiley-VCH, Weinheim, 2006; Ch. 15.
[2]
[18]
[19]
[20]
[21]
[3]
[4]
Russell, R.G.G. Bisphosphonates: Mode of action and
pharmacology. Pediatrics, 2007, 119, S150-S162.
Widler, L.; Jaeggi, K.A.; Glatt, M.; Müller, K.; Bahmann, R.;
Bisping, M.; Born, A.-R.; Cortesi, R.; Guiglia, G.; Jeker, H.; Klein,
R.; Ramseier, U.; Schmid, J.; Schreiber, G.; Seltenmeyer, Y.;
Green, J.R. Highly potent geminal bisphosphonates. From
pamidronate disodium (Aredia) to zoledronic acid (Zometa). J.
Med. Chem., 2002, 45, 3721-3738.
Hudson, H.R.; Wardle, N.J.; Blight, S.W.A.; Greiner, I.; Grün, A.;
Keglevich, G. N-Heterocyclic Dronic acids; applications and
synthesis. Mini-Reviews in Medicinal Chemistry, 2012, 12, 313-
325.
Rogers, M.J.; Frith, J.C.; Luckman, S.P.; Coxon, E.P.; Benford,
H.L.; Mönkkönen, J.; Auriola, S.; Chilton, K.M.; Russell, R.G.G.
Molecular mechanisms of action of bisphosphonates. Bone, 1999,
24 (Suppl.), 73S-79S.
Russell, R.G.G.; Croucher, P.I.; Rogers, M.J. Bisphosphonates:
pharmacology, mechanism of action and clinical uses.
Osteoporosis Int., 1999, 9, S66-80.
[5]
[6]
[7]
[22]
Yanvarevl, D.V.; Korovina, A.N.; Usanov, N.N.; Kochetkov S.N.
Non-hydrolysable analogues of inorganic pyrophosphateas
inhibitors of Hepatitis C virus RNA-dependent RNA-polymerase.
Russ. J. Bioorg. Chem., 2012, 38, 224-229.
Received: March 07, 2013
Revised: April 18, 2013
Accepted: April 22, 2013