The synthesis of gadoteridol is as follows: Compound (I) was reacted with DMF dimethylacetal to form the tricyclic intermediate (II). Following partial hydrolysis of (II), (III) was obtained and isolated in high quality and yield. (III) was reacted with tert-butyl bromoacetate in a basic media to obtain (IV), which was treated with aqueous sulfuric acid to effect removal of the tert-butyl and formyl protecting groups. (V) could be either crystallized or lyophilized. (V) was reacted with propylene oxide at pH 12 and excess propylene oxide was removed under vacuum upon completion of the reaction. (VI) was isolated by anion exchange chromatography with sulfate, and sulfate was then removed using a poly(4-vinylpyridine) resin. HP-DO3A was reacted with gadolinium oxide in water. Following concentration, excess gadolinium oxide was removed by filtration, and Gd(HP-DO3A)H2O was isolated by removing solvent. The product was then crystallized from methanol/acetone.

The synthesis of gadoteridol is as follows: Compound (I) was reacted with DMF dimethylacetal to form the tricyclic intermediate (II). Following partial hydrolysis of (II), (III) was obtained and isolated in high quality and yield. (III) was reacted with tert-butyl bromoacetate in a basic media to obtain (IV), which was treated with aqueous sulfuric acid to effect removal of the tert-butyl and formyl protecting groups. (V) could be either crystallized or lyophilized. (V) was reacted with propylene oxide at pH 12 and excess propylene oxide was removed under vacuum upon completion of the reaction. (VI) was isolated by anion exchange chromatography with sulfate, and sulfate was then removed using a poly(4-vinylpyridine) resin. HP-DO3A was reacted with gadolinium oxide in water. Following concentration, excess gadolinium oxide was removed by filtration, and Gd(HP-DO3A)H2O was isolated by removing solvent. The product was then crystallized from methanol/acetone.