Study On The Synthesis Of Novel Derivatives Of Bisphosphonates

Biphosphonate derivatives have a wide spectrum of applications. Their industrial usage include surfactant, polymeric materials, industrial water softener and anticorrosion agents. Moreover, Biphosphonate derivatives are the largest class of anti-osteoporosis agents in clinical use. They are used to treat a variety of bone resorption diseases, such as Paget’s disease, hypercalcemia due to malignancy, and osteoporosis etc. The development of biphosphonate drugs has been through three generations. The relationship of structure and function indicates: nitrogen-containing-side-chained heterocycles that constituted the third generation biphosphonate drugs (such as risedronate) exhibits about 10000 folds the efficacy of the first generation drugs of non-nitrogen-side-chained biphosphonates (such as Clodronate). Therefore, the synthesis and further study of nitrogen containing heterocyclic biphosphonates has considerable practical significance.1,2,3-triazole compounds are a class of azacycles that are highly active biologically. This class of compounds showed high anti-microbial and anti-HTV activity and are effective in treating arthritis, neurological disorder and tumor prevention. In order to obtain a novel, highly effective and highly selective anti-osteoporosis drug, in this paper, we successfully untilized Click-chemistry in introducing 1,2,3-triazole into biphosphonate compounds. In the same vein, we connected a naturally occurring structure to the biphosphonate structure using a triazole linker resulting in a series of novel biphosphonate derivatives.In this paper, we first reviewed the development of biphosphonate drugs. Subsequently, according to the principle of drug design, through the incorporation of 1,2,3-triazole with Click reaction, we propose a novel synthetic route for biphosphonate. Optimizations of the reaction conditions were performed as detailed below:1. Azides with varied substitution patterns were reacted with diethyl malonate and propargyl bromides via Click reaction. A series of nitrogen-containing heterocyclic bisphosphonates derivatives were synthesized and the reaction conditions were optimized. (1) In the preparation of 2-propargylmalonic acid diethyl ester, temperature, speed of titration and the molar composition of the reaction mixture should be strictly controlled; (2) Taking the reaction of ochlorbenzol azide and 2-propargylmalonic acid diethyl ester as a template, the reaction conditions for the preparation of precursors were studied and the optimal condition were achieved; (3) A series of new biphosphonates and 20 synthetic precursor were prepared.Their structures were characterized by ESI-MS, IR and NMR. 1H and 13CNMR attributions were corroborated by DEPT,1H-1H COSY, HSQC, HMBC2. Ethylidene bisphosphonate esters, propargyl phenyl ether and 7-(3-azidopropoxy) coumarin were reacted according to the optimized Click reaction condition. A series of N-BPs were synthesized and their structures were characterized by IR, ESI MS and NMR.