Bisphosphonates synthesis

Keywords. Carbonylphosphonate, Ketone, Carboxylate, Bisphosphonate, Synthesis troika acid, Phosphorylation, Monomeric metaphosphate, Nucleotide... 

Chen, R., Schlossman, A., Breuer, E., Hagele. G., Tillmann, C., Van Gelder, J.M., and Golomb, G., Long-chain functional bisphosphonates. Synthesis, anticalcification, and antiresorption activity. Heteroatom Chem., 11, 470, 2000. 

Mizrahi, D.M., Waner, T., and Segall, Y., a-Amino acid derived bisphosphonates. Synthesis and anti-resorptive activity. Phosphorus, Sulfur Silicon Relat. Elem., 173, 1, 2001. 

Scheme 18.16 Synthesis of neoxanthin (30) and mimulaxanthin (33) from the bisphosphonates 46/47 according to Eugster and co-workers [38, 54, 57]...

R. Niemi, J. Vepsalainen, H. Taipale, T. Jarvinen, Bisphosphonate Prodrugs Synthesis and in vitro Evaluation of Novel Acyloxyalkyl Esters of Clodronic Acid , J. Med. Chem. 1999,42, 5053-5058. 

Ohya K, Yamada S, Felix R, Fleisch H. Effect of bisphosphonates on prostaglandin synthesis by rat bone-cells and mouse calvaria in culture. Clin Sci 1985 69 403 11. 

Cohen H, Alferiev IS, Monkkonen J, et al. Synthesis and preclinical pharmacology of 2-(2-aminopjTimidinio) ethylidene-l,l-bisphosphonic acid betaine (ISA-13-l)-a novel bisphosphonate. Pharm Res 1999 16 1399-1406. 

Pillared polyethers and polyimines have been also described, which present sorbent and ion exchange properties [7, 56]. Immobilization of crown ethers and diaza crown ethers has been carried out with the bisphosphonate pillars strategy by using the co-precipitation synthesis [44, 58]. Exchange re-... 

Plicamycin (Mithracin), an inhibitor of RNA synthesis in osteoclasts, reduces serum calcium levels when infused over 4 to 6 hours every 3 to 4 days. Plicamycin s effects are slower than those of the bisphosphonates the drug is a bone marrow suppressant that can complicate clinical management if the patient is already receiving chemotherapy for the malignancy. 

FIGURE 6.13 Synthesis scheme of poly(2-hydroxy propylene spirocyclic pentaerythritol bisphosphonate or PPPBP. (From Chen, D.Q. et al., Polym. Deg. Stab., 88, 349, 2005.)... 

The first authentic synthesis of a bisphosphonic acid, l-hydroxyethane-l,l-bisphos-phonic acid (etidronic acid), was published by von Baeyer and Hofmann in 1897 [1], although it is possible that the same compound had already been obtained in 1865 by Menschutkin [2], The synthetic approach to BPs employed today differs only little from that used over a hundred years ago, and it is still based on the reaction of a carboxylic acid with phosphorus trichloride with the addition of some water [3], (Note BPs are usually represented as the free bisphosphonic acids the generic names given refer, however, to their salt forms.)... 

Lithium has been hypothesized to exert its therapeutic effects in the treatment of bipolar disorder by inhibiting inositol monophosphatase (IMPase), thereby causing a depletion of intracellular inositol. This in turn results in a reduction of the synthesis of the phosphoinositol required to sustain this signaling pathway. Several alicyclic and aromatic bisphosphonates, putative analogues of inositol 1-phosphate, were synthesized and tested, and some showed significant in-vitro potency [26]. 

Lecouvey M, Leroux Y. Synthesis of 1-hydroxy-1,1 -bisphosphonates. Heteroatom Chem., 2000, 11, 556-561. 

The synthesis and evaluation of binding ability of new model host compounds, bis-phosphonates (396) triphosphonates (397) and (398), with guanidine have been reported. The introduction of electron donating or withdrawing sub-stitutents in the 5-position of the parent bisphosphonate (396, X,Y = H) revealed the presence of Jt-cation interactions which contribute at least 0.5 kcal/mol for a single benzene guanidinium interaction. Even more effective was the introduction of a third phosphonate functionality at the correct distance, as shown in... 

Two methods for the first synthesis of partial amides (257), (258) and a partial amide ester (259) of etidronate have been developed (Figure 48). The preparation of 1,1-bisphosphonates from tris(trimethylsilyl)phosphite (260) and acid anhydrides (261) has been described. This synthesis allows a... 

Miscellaneous Reactions.- The phosphonate isostere (212) of (3 )-myo-inositol-1-phosphate has been prepared by olefination of the ketone (210) with the methylene bisphosphonate anion (211) followed by reduction and deprotection. 28 Further studies of the use of the phosphonate-based olefination of pyranoses in the synthesis of C-glycosides (e.g. 213)... 

Hutchinson, D,W, and Semple, G., Synthesis of alkylated methylene bisphosphonates via organothal-hum intermediates, J. Organomet. Chem., 291, 145, 1985. 

Niemi, R., Vepsalainen, J., Taipale, H., and Jarvinen, T., Bisphosphonate prodrngs. Synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid, J. Med. Chem., 42, 5053, 1999. 

Page, P.C.B., McKenzie, M.J.. and Gallagher, J.A., Simple synthesis of oxiranylidene-2,2-6A(phosphonic acid). Tetrabenzyl geminal bisphosphonate esters as useful intermediates, Synth. Commun., 32, 211, 2002. 

Griffiths, D.V., Hughes, J.M., Brown, J.W., Caesar, J.C., Swctnam, S.P., Cumming, S.A., and Kelly, J.D., The synthesis of l-amino-2-hydroxy- and 2-amino-l-hydroxyethylene-l,l-bisphosphonic acids and their /V-inelliylaled derivatives. Tetrahedron, 53, 17815, 1997. 

Turhanen, P.A., Ahlgren, M.J., Jarvinen, T., and Vepsalainen, J.J., Bisphosphonate prodrugs. Synthesis and identification of (1-hydroxyethylidene)-1,1-bisphosphonic acid tetraesters by mass spectrometry, NMR spectroscopy and X-ray crystallography. Phosphorus, Sulfur Silicon Relat. Elem., 170, 115, 2001. Pudovik, A.N., Batyeva, E.S., and Zamaletdinova, G.U., Reaction of a trimethylsilyl phosphite with O,O-diethyl acetyIphosphonate, Zh. Obshch. Khim., 43, 680, 1973 J. Gen. Chem. USSR (Engl. Transl.), 43, 676, 1973. 

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