138071-82-6

Take 5.0g of gadobutrol (Ⅰ) and 1.85g of lithium chloride into a three-necked flask, add 30ml of isopropanol, heat to 80-85℃ and reflux for 24h, then concentrate to dryness under reduced pressure. Add 30ml of anhydrous THF to the concentrate and stir to dissolve. Add 5.0g of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (Ⅱ), heat to reflux for 5 hours, concentrate to dryness under reduced pressure, add methyl tert-butyl ether and reflux to crystallize, filter and dry under vacuum at 50℃ to obtain 8.1g of intermediate (Ⅳ).

8.0g of intermediate (Ⅳ) was dissolved in 8ml of purified water by stirring. Separately, 7.37g of chloroacetic acid was dissolved in 8ml of purified water, and 3.27g of lithium hydroxide monohydrate was added at -5 to -5℃. The mixture was stirred until dissolved. The lithium chloroacetic acid solution was added dropwise to the intermediate (Ⅳ) solution at room temperature. After the addition was completed, the temperature was raised to 65℃, and about 2.8g of lithium hydroxide monohydrate was added in portions over 3 hours. The pH of the reaction system was controlled to be greater than 9. The reaction was continued for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, and the pH was adjusted to 3.5 with hydrochloric acid. After stirring for 0.5h, 160ml of ethanol was added, and the temperature was raised to reflux. The mixture was stirred and crystallized for 5 hours. After cooling to room temperature, the mixture was filtered and vacuum dried to obtain 8.3g of intermediate (Ⅳ). 8.2 g of intermediate (Ⅳ) was dissolved in 8 ml of purified water by stirring. The pH was adjusted to 3.5, and 3.02 g of gadolinium oxide was added. The mixture was heated to 95°C and reacted for 4 hours. After cooling to room temperature, the mixture was adjusted to neutral with lithium hydroxide. 80 ml of ethanol was added dropwise, and the mixture was heated to reflux and stirred to crystallize for 5 hours. After cooling to room temperature, the mixture was filtered and dried under vacuum to obtain 8.5 g of intermediate (Ⅵ), i.e., crude gadobutrol. 8.0 g of the crude product was dissolved in 8 ml of purified water by stirring at 70°C. 80 ml of ethanol was added dropwise over 1 hour. After the addition was complete, the mixture was heated to reflux and stirred to crystallize for 2 hours. After cooling to room temperature, the mixture was filtered and dried under vacuum to obtain 7.1 g of gadobutrol. The overall yield was 40.4%, and the HPLC purity was 99.9%.