Recent Work on the Synthesis of Phosphonate-containing, Bone-active Heterocycles

Copper-mediated displacements of allylic THP ethers on a bisphosphonate template

“…To begin exploration of this concept, the monophosphonate 16 was prepared (Scheme 5) by alkylation of an anion derived from diethyl methylphosphonate with geranyl bromide (3). Oxidation of phosphonate 16 with SeO 2 and t BuOOH, followed by reduction of the resulting mixture of aldehyde and alcohol with NaBH 4 , gave the desired alcohol 17 in modest yield.…”

“…1), especially in treatment of bone diseases such as osteoporosis, PagetÕs disease of the bone, myeloma, and bone metastases [1]. As a result, a number of methods have been developed for their synthesis, including reaction of a carboxylic acid with phosphorous acid and phosphorus trichloride [2], by alkylation of tetraalkyl methylenebisphosphonate [3], by reaction of lactams or amides with trialkylphosphites [4], by Michael-type addition to ethylidene bisphosphonate esters [5], by nucleophilic addition of a dialkyl phosphite to an acyl phosphonate [6], and very recently through treatment of a carbonyl compound with an excess of strong base and diethyl phosphorochloridite followed by oxidation with hydrogen peroxide [7]. Structure-activity studies on geminal bisphosphonates have indicated that their activity is highly dependent upon the non-phosphorus substituents of the central carbon [8], but many of these synthetic methods involve carbon-phosphorus bond formation which can require that structural diversity be incorporated early in the synthetic sequence.…”

Mode of Action of Herbicidal Derivatives of Aminomethylenebisphosphonic Acid. Part II. Reversal of Herbicidal Action by Aromatic Amino Acids

“…1), compounds 1-7, which were developed in Japan, are herbicidally active (Suzuki et al 1979). They are also promising agents for the treatment of bone disorders connected with calcium resorption (Ebetino et al 1990). In an earlier paper we showed that the herbicidal action of these compounds is accompanied by impairment of anthocyanin biosynthesis (Lejczak et al 1996).…”

Chemometric-assisted determination of some bisphosphonates and their related substances in pharmaceutical forms by ion chromatography with inverse UV detection

“…It is thus possible that some synthesis related substances may appear in raw or finished product as impurities [6][7][8][9][10][11][12]. Degradants from P-C-P bridge hydrolysis could be also found [13].…”

“…They have been prepared by reaction of carboxylic acid with phosphorus acid and phosphorus trichloride [5], by alkylation of tetraalkyl methylenebisphosphonate [6,7], by reaction of lactams or amides with trialkylphosphites [8] by Michael-type addition to ethylidene bisphosphonate esters [9,10] and by nucleophilic addition of a dialkyl phosphite to an acyl phosphonate [11,12].…”