Methylenebisphosphonates synthesis

Thymidine dimers in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring have been synthesized and have been incorporated into oligodeoxynucleotides <02HCA2847>. The synthesis of mono- and bis-3-substituted thymidine derivatives with a polycyclic tetrazole linker (l,5-bis(tetrazol-5-yl)-3-oxapentane) has been reported <02TL1901>. a-Methylene tetrazole-based peptidomimetics were synthesized for inhibition studies of HIV protease <02JCS(P1)172>. A catalytic amount of tetrazole was found to be useful in the syntheses of symmetrical P,P -dialkyl partial esters of methylenebisphosphonic acid from the corresponding acid chloride via a facile two-step, one-... 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

Nucleoside Polyphosphates. - The preparation of the phosphonate analogues of IpJ and IpsI (130) and (131) has been described. Various methods for the efficient synthesis of these compounds have been examined. The most convenient method employed tris(imidazolido)phosphate and inosine 5 -methyl-enediphosphonate, which had been prepared from 2, 3 -isopropyledeneinosine and methylenebisphosphonic dichloride. ... 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

Makarov MV, Leonova ES, RybaUdna EY, Khrustalev VN, Shepel NE, Roschenthaler GV, et al. Methylenebisphosphonates with dienone pbarmacophore synthesis, structure, antitumor and fluorescent properties. Arch Pharm 2012 345(5) 349—59. 

Haelters and co-workers have reported the synthesis of a series of new functionalized tetraethyl methylenebisphosphonates (105) with long chain aliphatic groups in order to increase their lipophilicity and bioavailability Subsequent allylation of the latter with allyl bromide afforded the corresponding bisphosphonates (106) (Scheme 35). The reactivity of the allyl group was further utilized to give access to other substituted bisphosphonates (107), functionalized by diverse groups including alcohol, aldehyde, carboxylic acid, epoxide and amine. 

Several new improved syntheses of therapeutically active 1-hydroxy-methylenebisphosphonates have appeared in the literature of the passed period. McKenna et al. have demonstrated simple and efficient method for synthesis of nitrogen-containing heterocyclic (risedronate, zoledronate) and aminoalkyl (pamidronate, alendronate, neridronate) 1-hydroxy-methylenebisphosphonates (447) using microwave irradiation from carboxylic acids (446). These compounds are useful in the treatment of osteoporosis and other bone diseases (Scheme 110). ... 

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