Synthesis of Symmetrical Methylenebis(Alkyl Hydrogen Phosphonates) by Selective Cleavage of Methylenebis(Dialkyl Phosphonates) with Morpholine

Abstract

The preparation of partial esters of methylenebisphosphonic acids has been of recent interest due to their potential therapeutic applications. This paper describes a convenient method to prepare symmetrical methylenebis(alkyl hydrogen phosphonates) by the selective cleavage of the corresponding methylenebis(dialkyl phosphonate) with refluxing morpholine. The effects of structural variations on the amine as well as the substrate have been investigated to understand the scope and limitations of this reaction. A superior approach to hindered bisphosphonic acid esters involves the cleavage of their dimethyl esters, 4, using morpholine. This method is also useful to access a number of C-alkyl dialkyl methylenebisphosphonic acids such as 6. This study clearly shows that cleavage with morpholine is convenient, inexpensive, and allows for the preparation of a variety of P,P'-disubstituted partial esters in good yields and high purity.

Dialkyl Bisphosphonate Platinum(II) Complex as a Potential Drug for Metastatic Bone Tumor

“…DEBP-Pt, however, has no free phosphate group. We anticipated that an intermediate was formed by partial hydrolysis of DEBP-Pt and equilibrium between DEBP-Pt and an intermediate exists in an aqueous solution of DEBP-Pt similarly to carboxylate platinum complexes such as carboplatin 19) and oxaliplatin 20) (Chart 2 12) the estimated bond energy between platinum and phosphate is lower than that between chloride and platinum, and DEBP-Pt is thought to be converted to its active form (intermediate or diaqua platinum complex) more easily compared to cisplatin. Hence, DEBP-Pt was expected to exert equivalent or greater antitumor activity than cisplatin.…”

Electrophilic polyfluoroalkylating agents based on sulfonate esters

“…Methylene bis(diethyl phosphonate) was converted into the corresponding salt by reaction with potassium tert-butoxide in toluene and reacted with polyfluoroalkyl triflate. Monopolyfluoroalkylated bisphosphonate 67 [65] was obtained in 42% yield (Scheme 23).…”

“…They are mentioned in a patent [63] and in two articles [64,65]. Their synthesis is based on the same principle as those with methylene or ethylene spacers.…”

“…Fluorous gallate 66 was then converted into the corresponding benzylalcohol and benzaldehyde (Scheme 23). 3-(Perfluorooctyl)propyl triflates was used in preparation of polyfluoroalkylated bisphosphonate 67 [65]. Methylene bis(diethyl phosphonate) was converted into the corresponding salt by reaction with potassium tert-butoxide in toluene and reacted with polyfluoroalkyl triflate.…”

Synthesis of medronic acid monoesters and their purification by high-performance countercurrent chromatography or by hydroxyapatite

“…The synthesis of triesters [23] and symmetrical diesters [24] from medronic acid tetraesters has been achieved previously by using tertiary and secondary amines, for example. Unfortunately the same strategy cannot be applied to the synthesis of monoesters.…”