Amidation Bisphosphonate

The bisphosphonate - upon reduction with lithiumaluminum hydride in ether at 0°C - produced the amide functionalized primary bisphosphine (1) in good yields [45]. This reaction proceeded to reduce the amide group in 1 to produce the amine functionaUzed primary bisphosphine (2) in <5% yields. The amido bisprimary phosphine 1 is an air stable crystalline solid whereas the amine compound 2 is an oxidatively stable liquid. Separation of 1 and 2 in pure forms was achieved using coliunn chromatography. The amidic bisprimary phosphine 1 was crystallized from chloroform and exhibits remarkable stability not only in the solid state but also in solution as well. The crystal structure of the air stable primary his-phosphine 1 as shown in Fig. 1 is unprecedented to date. 

Phosphoramidates rearrange into a-aminophosphonates using chiral lithium amide bases e.g. 31 afforded aminophosphonate 86 from phosphoramidate 85 in 13% ee and 65% yield (Scheme 61)104. A slightly higher optical purity of 26% (55% yield) was obtained with chiral (R. R)-3 as base. The application of (—)-sparteine and BuLi gave 13% ee and a yield of 30%. A higher level of enantioselectivity was reached when a bisphosphonate (87) was reacted with (R,R) 3 in THF. Although the yield was only 30%, aminophosphonate 88 was obtained in 35% ee (Scheme 61). 

Two methods for the first synthesis of partial amides (257), (258) and a partial amide ester (259) of etidronate have been developed (Figure 48). The preparation of 1,1-bisphosphonates from tris(trimethylsilyl)phosphite (260) and acid anhydrides (261) has been described. This synthesis allows a... 

A new type of bisphosphonates 1 with various aromatic rings on the side chains linked by amide bonds is synthesized [140]. The driving force for these studies is the assumption that the introduction of a cyclic group on the side chain may increase the antiresorptive potency of the bisphosphonates. 

Bisphosphonates have been prepared starting either from the corresponding nitriles or from the respective amides [157]. 

Functional properties of the carboxyl group have been used to modify it with osteofilic bisphosphonate fragments, as exemplified by structural modifications of moxi-, gati- and ciprofloxacin are developed [62], Derivatives of these fluoroquinolones 21, containing bisphosphonate ester, thioester or amide groups have been obtained (Scheme 11). Their abilities to contact bones and to recycle thus active medicinal component have been studied. It has been shown that bisphosphonate derivatives of fluoroquinolones are osteotropic predecessors for prevention of osteomielit. 

---