Studies On Pilot-scale Experiments And Impurities Of Zoledronic Acid

Research Background:Zoledronic acid is one of the third generation diphosphate drugs, which has more than tenyears of clinical application history. Zoledronic acid is used for treat malignant hypercalcemia,postmenopausal osteoporosis, anti.cancer, Paget’s disease and other metabolic bone disorders.dverse effects is small, including gastrointestinal tract, hypocalcemia, fever, acute kidneyinjury.The most common adverse reactions is fever. It has become a kind of important clinicaltreatment of new drugs since market share has been increasing qulckly, which can treatosteoporosis,hypercalcemia and cancer pain caused by bone metastases.Zoledronic acid is synthesized existing the following deficiencies. The solvent is usedcontai-ining greater toxicity and the price is expensive, Some have serious effects on humanhealth and the environment, even special agent can not buy that need to synthesize in theexperiment. the costs are high. Reaction curing is serious,which requires a phase transfer catalyst.The yield is low. In response to these shortcomings, we has developed the synthetic method ofzoledronic acid in our laboratory. The solvents very cheap and low toxicity that are sold in themarket. It meets atomic economics and green chemistry requirements and the cost is lower.On these basis, we research on pilot-scale experiments. The purpose of the pilot-scale ofzoledronic acid to provides important data for the factory’s production. In addition, we discussresidue of imidazole in zoledronic acid.The basic experimental operation is as follows, Imidazole reacts with potassium hydroxide inacetone, then adding bromine ethyl acetate to container. Ethyl2-(1H-imidazol-1-yl)acetate isformed after mixturing some time. We filter solution and rotary evaporated to get crude product.The mixture acetone ethyl2-(1H-imidazol-1.yl)acetate and water and ethanol to get imidazoleacetic acid,hydrolyzing in the presence of Water.Acetone was added to the reaction olution,whichis separated to give the product. The crude product is recrystallized to give pure product by ueingacetone and water. The present inv-ention mix imidazole acetic acid, phosphorus trichloride to get bisp-hosphonic acids, hydrolyzing under acid condition.Distillation under reduced pressure to geta concentrated solution that was added dropwise into acetone to give product.The specific contents are as follows:(1)We study pilot-scale experiments of zoledronic acid.The times of Imidazole-1-aceticacid are20,40,80,160,320,640, then640times was done three times to verify the stability andreproducibility.. The result show that:yield of the pure imidazole acetic acid is76%, the yield isstable triplicate,and the purity is99.856%by high performance liquid chromatography,(2)The times of zoledronic acid are25,50,100,250,500, then500times was done threetimes to verify the stability and reproducibility. The result show that:yield of the zoledronic acid is84%,the yield is stable triplicate, and the purity is99.932%by high performance liquidchromatography,(3)Document reports that the impurities of zoledronic acid are imidazole and imidazoleacetic acid，we discusse imidazole residue situation in the final product. We use HPLC to studymethology validation of imidazole. Studies have shown that the present process for thepreparationof zoledronic acid donot contains impurity of imidazole.