Technics Optimization Of Synthesis Of N-nicotinoyl- Iminodiacetic Acid And Pharmacological Activity

It has been well established that irradiation cells under oxygen deprived conditions increase the resistance of those cells to sparsely ionizing radiation. These cells will influence the response of those tumors to radiation and potentially lead to relapse and metastasis of malignant tumors. Searching for radio-sensitizers which have higher effective and lower toxicity is an urgent task in radiation treatment. To find more effective radiosensitizers than nicotinamide, Pharmacology Research Lab of Institute of Radiation Medicine of Chinese Academy of Medical Sciences did the structure modification of nicotinamide. The method was attaching active amino acid into the side chain of nicotinamide, thus synthesized a series of nicotinoylamino acid compounds. Among these, N-nicotinoyl-iminodiacetic acid has the best radiosensitization effectiveness.However, the technics of synthesis of N-nicotinoyl-iminodiacetic acid consumed longer time, temperature control was unstable, carrying out solvents recycling was not safe and had lower recycle rate, and the decomposition was severe thus leading to lower productivity. So as to achieve pilot scale production and industrialized scaled-up production, we decided to improve the technics of synthesis and purification.This project was going to achieve this aim from several aspects, including:reaction temperature, pH range, purification methods and solvent recycling. Also, we used the improved technics to carry out scaled-up experiments. After a set of systematic trials, the improved technics conditions are as follows:the temperature should be controlled at 0-5℃and maintained by the low temperature liquid circulating pump; when recycling the ether solvent by rotary evaporation, using the-15℃ethanol as low temperature circulation fluid in the condenser pipe and the recovery rate is 75%; In the step of synthesis of N-nicotinoyl-iminodiacetic acid, the pH should be maintained 7-8, reaction temperature around 15℃, thus the reaction time was reduced to 15-16h and the yield rate could reach 60%-80%. Finally, we could gain conforming product with the purity above 95%.The production and purification technics after optimization had reduced the reaction time and decreased the side products. Also, it's easy to operate, could reach a higher yield rate and increased the purity. Satisfying the technical requirements of class 1 chemical medicines and providing drug for further pharmacokinetics and pharmacological researches. At the same time, we tested its synergized anti-tumor effect with cis-platinum.