Synthesis of imidazol- 1-yl-acetic acid hydrochloride: A key intermediate for zoledronic acid

• Santosh Kumar Singh,
• Narendra Manne,
• Purna Chandra Ray and
• Manojit Pal

Beilstein J. Org. Chem. 2008, 4, No. 42, doi:10.3762/bjoc.4.42

• -acetic acid hydrochloride was achieved via N-alkylation of imidazole using tert-butyl chloroacetate followed by a non-aqueous ester cleavage of the resulting imidazol-1-yl-acetic acid tert-butyl ester in the presence of titanium tetrachloride. The synthesized imidazol-1-yl-acetic acid hydrochloride was

• then utilized to prepare zoledronic acid. Keywords: ester; N-alkylation; imidazol-1-yl-acetic acid hydrochloride; zoledronic acid; Introduction Zoledronic acid (Z, Figure 1) [1][2][3][4][5][6][7] is a third-generation bisphosphonate (or diphosphonate) derivative characterized by a side chain that

• reacting with H3PO3 and POCl3 according to the procedure shown in Scheme 2. Conclusion In conclusion, we have reported a practical two-step direct synthesis of imidazol-1-yl-acetic acid hydrochloride, a key intermediate for the synthesis of zoledronic acid, in more than 5 g scale. Unlike earlier routes