The synthetic process of zoledronic acid(1)was improved.With commercially available imidazole(3)and ethyl chloroacetate(4)as raw materials,the intermediate imidazol-1-acetic acid hydrochloride(2 hydrochloride)was obtained by N-alkylation and hydrolysis reaction through a"one pot method"under the presence of potassium tert-butanol.Crude 1 was then synthesized from 2 hydrochloride,with phosphorus trichloride as the phosphonation reagent.The yield was raised from 46％to 87％by increasing the amounts of methanesulfonic acid and phosphorus trichloride and prolonging the reaction time.After recrystallization from water and acetone,1 was obtained in 68％yield(based on 3)with HPLC purity of 100.0％.The improved process has the characteristics of low production cost,safer and simpler operation and high yield,which makes it amenable for industrial production.
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