Bisphosphonic acids reactions

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.)... 

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. 

In continuation of studies on the formation and reactions of 1-hydroxyalkyl-l,1-bisphosphonic acid cyclic esters (Organophosphoms Chemistry, 1988, j, 161), the a,u-dioxoalkanediphosphonic tetraesters (167 n=3-8) have been shown to react with more hydrogen phosphonate to give the a, (u-dihydroxy-a, o, u), co-bis [ bis phosphonic acid)] esters (168) cross-reactions e.g., between (167b) and dimethyl phosphonate (affording the same product as that obtained from (167a)... 

Many communications have concentrated on specific amino phosphonic acids or derivative types. Thus, esters of phosphonoaminoacetic add were obtained by the reactions between trialkyl (ethyl) phosphite and (218) and which are thought to proceed via the phosphorane (219). A sequence has been presented for the preparation of the mono- and di-benzyl esters of N-chz protected (a-aminoben-zyl)phosphonic acid. A synthesis of (aminomethylene)bisphosphonic acid from dibenzylamine, dibenzyl hydrogenphosphonate and triethyl orthoformate has been noted and the asymmetric hydrogenation of (220) in the presence of chiral phosphine catalysts yields samples of (221) with e.e.s of 63-96%. The pyrrolidine-based compound (222) has been prepared from methyl S)-N-methoxycarbonyl-4-oxo-2-pyrrolidinecarboxylate and iV-coupled 4-amino-butanal diethyl acetals were the starting materials in syntheses of the pyrrolidine-2-phosphonic add derivatives (223) in which Z represents the iV-protected amino add or peptide moiety. ... 

It is evident that the interaction of a phosphorus(III) triester and the alkylating species RX can be pictured as an S 2 process (reaction 2) or, for those alkylating reagents capable of forming a carbocation, as an S l process (reaction 3). Several reactions testify to the importance of carbocationic carbon for the Michaelis-Arbuzov reaction in pursuance of its normal course they include the ease of reaction of cyclopropene dihalides, already encountered, and the ready formation of complexes with species having particularly weakly nucleophilic counter ions. Phosphonic acid formation also takes place with cyclic azonium salts and related ions. 9-Chloroacridine reacts with triethyl phosphite to afford a product thought to be the bisphosphonic acid ester 49 The related phosphonic esters 51 are obtainable when the onium salts 50 (X = NH, NR, O or S) are treated with trimethyl... 

Reactions between dialkyl hydrogenphosphonates and (l-oxoalkyl)phosphonic diesters in the presence of a trace of basic catalyst, normally triethylamine or sodium alkox-ide, give rise to tetraakyl esters of (l-hydroxyalkylidene)bisphosphonic acids (269) in a manner similar to the behaviour of the hydrogenphosphonates towards simple aldehydes or ketones" ". However, following the initial observations of this interaction, it soon became apparent that, based on H NMR evidence, the isolated compounds did not possess the stated alkylidenebisphosphonate structure but were, in reality, the products of a... 

The synthesis of homologues of (hydroxymethylene)bisphosphonic acid may be achieved through reactions between other carboxylic acids, PCI3 and water at 130 and the use of carboxylic esters is also feasible". (Hydroxymethylene)bisphosphonic acid and its ethers are obtainable from tetraalkyl pyrophosphites and alkyl formates in the presence of BF3 at 20-130 Yet a further reactant combination consists of an alkanoic ester, and P4O6-BF3, which produces glasses, but from which the bisphosphonic acid may be extracted with boiling dilute HCl. ... 

The reaction of chloroacetamide with phosphorus trichloride and phosphorous acid is reported to lead to l-amino-2-chloroethane-l,l-bisphosphonic acid . Treatment of this compound with base caused loss of ammonia with the formation of phospho-noacetylphosphonic acid as the sodium salt. The reaction has been rationalized by the mechanism depicted in equation 37 ... 

It was proposed that this is a general characteristic of all 2-hydroxyalkane-l,l-bisphos-phonic acids. Indeed, a similar result was produced by the product of the reaction of hydroxyacetonitrile with phosphorous acid, l-amino-2-hydroxy-l,l-bisphosphonic acid, which decomposed on acidification to give acetylphosphonic acid, presumably via the corresponding enamine (equation 39f. ... 

Another case in which a geminal bisphosphonate is converted in to an acylphosphonate is the thermal rearrangement of silylated 3-amino-l-hydroxypropane-l,l-bisphosphonic acid. This reaction yields 3-phosphonopropionylphosphonic acid, along with some byproducts, the formation of which is rationalized in equation 40. 

A-derivatives of (2-amino-1-ethylidene)bisphosphonic acid. The addition reactions... 

Amino-l-hydroxyethylene-l,l-bisphosphonic acid 2 has been synthesized from Af-phthaloylglycme [142]. Treatment of Af-phthaloylglycme with thionyl chloride gave the corresponding acid chloride, which on reaction with trimethyl phosphite, furnished a-ketophosphonate 1. Addition of dimethyl H-phosphonate to the carbonyl gronp of 1 gave 2. 

In the course of synthesising enantioenriched y-keto gem-bisphosphonates having anti-arthritic and anti-inflammatory activities, Barros and Phillips have finalised organocatalytic asymmetric Michael additions of cyclic ketones to vinyl gem-bisphosphonates. The reactions were performed in the presence of (iS)-( + )-l-(2-pyrrolidininylmethyl)pyrrolidine as an organocatalyst and benzoic acid as an additive, leading to the expected Michael products in high yields, excellent diastereoselectivities (> 98% de) combined with enantioselectivities... 

Due to the biological activity of bisphosphonic acids, a vast array of derivatives and precursors have been generated including bile salts (Scheme 4.166) [255]. The overall process started with protection of the alcohols on the parent bile salt through the addition of formic add. Once suitably protected, the addition of thionyl chloride converted the carboxylic acid into an add chloride. Since these conversions are typically carried out using an excess of the thionyl chloride, the ranoval of unreacted material can be particularly troublesome. In these reactions, the ranoval of the excess thionyl chloride was achieved through repeated trituration with benzene. The final steps in the synthesis entailed... 

Turhanen has reported a synthesis of novel (co-allqmyl-l-hydrojgr-l, -diyl)bisphosphonic acid tetramethyl esters (398), their dimethyl esters (399), and trimethyl ester derivatives (400), as useful substrates in click chemistry. Thus, the reaction of bisphosphonate dimethyl ester (399) (n = 2) and tri methyl ester (400) (n = 2) with azide functionalised triethylene glycol (401) afforded triethylene glycol-bisphosphonate conjugates (402) and (403), respectively (Scheme 122). ... 

The reaction of isonitriles (259) with triethyl phosphites in the presence of hydrogen chloride gave tetraallgrl iV-substituted aminomethy-lenebisphosphonates (261) via iV-methylideneaminium (isonitrilium) salts (260). Hydrolysis or dealkylation of these tetraall l esters (261) gave the corresponding JV-substituted bisphosphonic acids (262) in 77-98% yields (Scheme 92). ... 

Adverse reactions with the bisphosphonates include nausea, diarrhea, increased or recurrent bone pain, headache, dyspepsia, acid regurgitation, dysphagia, and abdominal pain. 

ISPHOSPHONATES The nurse monitors the patient taking the bisphosphonates for any adverse reactions such as nausea, diarrhea, increased or recurrent bone pain, headache dyspepsia, acid regurgitation, dysphagia, and abdominal pain. Analgesic maybe administered for headache Notify the primary health care provider of adverse reactions such as the return of bone pain or severe diarrhea... 

Mention might be made of a useful synthesis which is based on the Abramov-type reaction between a hydrogenphosphonate and a dialkyl (l-oxoalkyl)phosphonate, formed in situ, to produce tetramethyl (l-hydroxy-4-phthalimido)butane-l,l-bisphosphonate, readily deprotected to give the free amino phosphonic acid 364. ... 

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