To a three-necked flask, 1,4,7,10-tetraazacyclododecane (100 g, 0.58 mol) and 10 ml of deionized water were added and mixed with stirring. The pH of the reaction system was adjusted to 8.5 by slow dropwise addition of 30% potassium hydroxide solution.Subsequently, chloroacetic acid (263 g, 2.78 mol) was added and the pH was adjusted again to 8.5 using 30% potassium hydroxide solution.The reaction mixture was heated to 80 °C and kept for 24 h, during which time the pH was continually monitored and adjusted to maintain a pH value between 8.5 and 9. After completion of the reaction, it was cooled to room temperature and the pH was adjusted to 2 by adding concentrated hydrochloric acid, at which time a white precipitate was produced. The precipitate was collected by filtration and the filter cake was recrystallized from a mixed water-ethanol solution. The resulting crystals were washed with ethanol and ether in turn, and 183 g of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) crystals were obtained after drying with a yield of 78%.
