Methylenebisphosphonic acid

Thymidine dimers in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring have been synthesized and have been incorporated into oligodeoxynucleotides 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-... 

Stir the solution of pyrophosphoric acid (obtained in step 1) in an ice bath and add a 10% solution of tetra-/7-butylammonium hydroxide dropwise until pH 7.3 is reached (note use a pH meter). This will be around 50 mL (for methylenebisphosphonic acid and difluoromethylenebisphosphonic acid, the solutions should be titrated to pH 10 and 7.3, respectively). 

Blackburn, G. W., England, D. E. and Kolmann, F. (1981) Monofluoro- and difluoro-methylenebisphosphonic acids isopolar analogues of pyrophosphoric acid. J. Chem. Soc., Chem. Commun., 930-932. 

The first examples of supercharged nucleotide analogues (85-87) have been described, in which methylenebisphosphonic acid containing an additional ioni-sable acidic function has been incorporated into p,y-bridged derivatives of adenosine triphosphate. The compounds and their protected precursors were obtained following acid-catalysed reaction of the respective precursors (88-90) with adenosine 5 -phosphoromorpholidate in pyridine in yields of 80,75 and 25%. 

A particularly important example of a gem-diphosphonic acid is, in fact, the simplest, namely methylenebisphosphonic acid (39) n- 1). The interaction of diiodomethane with excess triisopropyl phosphite at 150-160 °C has provided 50-60% of tetraisopropyl meth-ylenebisphosphonate , but marginally better yields are reported to be obtainable if dibro-momethane is employed Lower yields of the tetraethyl ester are obtainable using triethyl phosphite, and it should also be noted that a difference in the ratio of reactants is liable to provide dialkyl (halomethyl)phosphonates (Chapter 3, Section II. A). A similar procedure has provided the tetraethyl esters of a,co-alkanebisphosphonic acids (39) n - l-10) In a like manner, Dahl and Block " have obtained methylenebisphenylbisphosphinic acid (40) via its diisopropyl ester (not isolated) from diiodomethane and diisopropyl phenylphos-phonite. 

Vinylidenebisphosphonic acid derivatives and homologues have been prepared from methylenebisphosphonic acid tetraalkyl esters by the routes A, B, and exemplified in Scheme 27. The [2,2-bis(alkylthio)ethenyl]bisphosphonic tetraethyl esters provided a source of novel (enediamine)bisphosphonic esters. The novel compound (260)... 

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. 

As in all Michaelis-Arbuzov and Michaelis-Becker reactions, the usual order of decreasing reactivity at the carbon-halogen bond, I > Br > Cl > F, applies with carbon-fluorine bonds tending to be unreactive, other than in exceptional circumstances. Even for diiodomethane, the most reactive dihalomethane, reactions with trialkyl phosphites can be made to yield esters of (iodomethyl)phosphonic acid (11 R = O-alkyl, R = alkyl, n=, X = I or in the presence of more phosphite ester, the methylenebisphosphonic ester 12... 

In a typical Wittig process, the lithium salt of tetramethyl methylenebisphosphonate acts upon the cyclic ketone 305 to give 306 further steps which consist essentially in reduction (Pt02, H2), de-esterification at phosphorus (Mc3SiBr) and further deprotection (aq. F3CCOOH), give racemic w> o-inositolmethylphosphonic acid (307 R also obtain-... 

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... 

Several steps are required to convert D-mannose (244) into compound (245) from which, by phosphorylation with diphenyl phosphorochloridate and triethylamine, followed by hydrogenolysis, (246) may be obtained. Attempts to modify this latter substance at C(l) so as to introduce a further phosphorus-containing function have not been. successful. The bis(isopropylidene) derivative (247) reacted with tetraethyl methylenebisphosphonate to give (248), together with its C(l) epimer and (249). Treatment of the anomers of (248) with p-toluenesulphonic acid in acetone so as to remove the 4,6-isopropylidene group, and further phosphorylation (same reagents). 

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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