Synthesis Of Novel 1,2,3-Triazole Containing Bisphosphonates

Nitrogen-containing biphosphonate (N-BPs) drugs are used to treat a variety of bone resorption diseases, such as osteoporosis, Paget’s disease, and hypercalcemia due to malignancy. They are thought to act by inhibiting the enzyme farnesyl diphosphate synthase, resulting in inhibition of protein prenylation in osteoclasts. It is worth mentioning that most of the highly potent third-generation BP drugs contain the nitrogen heterocyclic component in their molecular structures, as in risedronate and zoledronate, and for the treatment of bone diseases associated with excessive resorption, the cyclic nitrogen biphosphonates (N-BPs) are up to 10,000-fold more active than the first-generation non-nitrogen containing BP, for example, etidronate. Therefore, the purposeful synthesis of new members of cyclic nitrogen containing N-BP family is of current interest for further development of more potent drugs.With respect to introducing 1,2,3-triazole groups into organic molecules, copper(I)-catalyzed 1,3-dipolar Huisgen cycloaddition (CuAAC) reaction of azides and terminal alkynes, one of the most popular reactions within the click chemistry concept, discovered by the groups of Sharpless and Meldal is a useful approach leading to 1,4-substituted products with high regioselectivity. Our group has recently discovered that the highly regioselective copper(Ⅰ)-catalyzed 1,3-dipolar cycloaddition reaction rate can be notably accelerated at room temperature in the presence of ultrasound irradiation. Therefore, this paper envisages that the 1,2,3-triazole to introduce to biphosphonate derivatives.Recently development for bisphosphonate drugs were first reviewed in chapter 1. In chapter 2, (1) 31P-NMR spectroscopy is used for studies of Michael addition reaction between NaN3 and ethylidene bisphosphonate, the results show that AcOH: H;O=1:1 (v.v) is the best solvent and adducts decomposed at pH= 4.69, this problem has been addressed by developing one-pot procedures where the organic azide is generated in situ. (2) the reaction between phenylacetylenes NaN3 and ethylidene bisphosphonate was selected as a model reaction for optimizing the reaction conditions by investigating the influence of ultrasound on the effeciency of cycloaddition with different Cu(I) salts、amount of the catalyst and reaction temperature. The results show that①CuSO4·5H2O/NaAsc is the best catalytic efficiency among tested Cu salts;②CuSO4·5H2O (10mol%)/sodium ascorbat (20 mol%) has the best catalytic efficiency among the tested amount of the catalyst;③the optimal reaction temperature was 45℃. Eighteen N-attached 1,2,3-triazole containing bisphosphonate were synthesized under the optimized condition, their structures were confirmed by IR, ESI MS and NMR. The structures of 1,4-disubstituted N-attached 1,2,3-triazole containing bisphosphonate were confirmed by 2D NMR.In chapter 3, the synthesis of propargyl-substituted bisphosphonate based on the alkylation of methylene bisphosphonate by propargyl bromide(with deprotonation by NaH) being reported in the literature. Then,12 novel biphosphonate derivatives containing 1,2,3-triazole moiety were synthesized via Cu(Ⅰ)-catalyzed 1,3-dipolar Huisgen cycloaddition between propargyl-substituted bisphosphonate and organic azides. Their structures were validated by IR, ESI MS and NMR.