Abstract
A convenient and environmentally-friendly protocol for the preparation of imidazol-1-yl-acetic acid hydrochloride is described via solvent-free N-alkylation of imidazole by tert-butyl chloroacetate, the obtained imidazol-1-yl-acetic acid tert-butyl ester was hydrolyzed in water and treated with hydrochloric acid to get imidazol-1-yl-acetic acid hydrochloride in good yields. Unlike the previously reported methods, this two step process is completely free from the use of hazardous solvents, besides, it has high yielding and been characterized by simple and easy work-up procedure. Imidazol-1-yl-acetic acid hydrochloride produced by the described method is converted into zoledronic acid monohydrate of medicinal use.
Highlights
Imidazol-1-yl-acetic acid hydrochloride (4) is a key intermediate for synthesis of (l-hydroxy-2imidazole-l-yl-phosphonoethyl)-bisphosphonic acid (Zoledronic acid) (1, Scheme 1), a third generation and a very popular bisphosphonate derivative
According to the synthetic method reported by Yadav et al [5], methyl imidazol-1-ylacetate was synthesized by the addition of methyl chloroacetate to a mixture of imidazole, potassium carbonate (K2CO3) and potassium iodide (KI) in the media of dichloromethane (DCM), resulting imidazole-1-yl-acetate which was de-esterified in water and isolated from methanol, using solvents in both steps
Synthetic method by Pulla Reddy et al [6] include addition of methyl chloroacetate to a mixture of imidazole, potassium carbonate (K2CO3) and tetrabutylammonium bromide (TBAB) in the solvent media comprised of DMF and toluene, after the completion of the reaction, it was worked up by extraction in ethyl acetate and evaporation of ethyl acetate to afford ester intermediate which was hydrolyzed in water
Summary
Imidazol-1-yl-acetic acid hydrochloride (4) is a key intermediate for synthesis of (l-hydroxy-2imidazole-l-yl-phosphonoethyl)-bisphosphonic acid (Zoledronic acid) (1, Scheme 1), a third generation and a very popular bisphosphonate derivative. Zoledronic acid is used to treat some diseases including osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, and Paget’s disease of bone. Zoledronic acid (1) is used along with cancer chemotherapy; it neither suppresses nor stops cancer spreading. Zoledronic acid is used to treat bone related implications in patients who are suffering from cancer. It is widely used as a bone resorption inhibitor. It may decrease the amount of calcium released from bones into the blood [1,2,3,4]
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