Synthesis Process Research For Tigecycline

Tigecycline, which belongs in tetracycline antibiotics, has broad-spectrum antibacterial activity and is difficult to form drug resistance.Its chemical entity patent will expired in 2016, moreover, the huge potential mark of tigecycline is very substantial. According to above situation, the synthesis of Tigecycline is researched and developed.During the initial developmentstage, we have retrieved large numbers of literatures and patents. After that, a lot of experiments were performed to inspect the reaction condition in each step, such as reaction time, temperature and pH, etc. At last, a reasonable synthetic route of Tigecycline was obtained.1.Optimized Synthesis of 9-nitro-minocycline: Weight ratio of Minocycline, concentrated sulfuric acid and fuming nitric acid is 1:5.5:0.16. Controlling the reaction temperature at-5~-10℃. 9-nitro-minocycline is obtained and its purity is not less than 80%, which can be used in next step.2.Optimized Synthesis of 9‐amino‐minocycline: The reaction was performed with 5% Pd/C and 0.15~0.2MPa hydrogen at 20~30℃. 9‐amino‐minocycline was obtained and its purity is not less than 80%. Weight yield from minocyclineto 9‐amino‐minocycline is 110‐120%.3.Optimized Synthesis of tigecycline sulfate: The ratio of 9‐amino‐minocycline and N‐t‐butylglycine acid chloride hydrochloride is 1:1.1. Controlling the temperature at 0 ℃.The purity of tigecylcine sulfate is more than 80%, weight yield is more than 80% as well.4.Optimized Synthesis of tigecylcine crude: Controlling the pH=7.2 when isolating, the crude Tigecycline was obtained and its purity is not less than 96%5.Optimized Synthesis of tigecycline: Surry with methanol‐ acetone 1:1, final API purity is more than 99%, unknown impurity is less than 0.1%.The total weight yield from Minocyline to tigecycline is 30%~40%, material cost is controlled below 50,000, which reduced Production cost greatly.In conclusion, we have optimized the synthesis process and simplified the production operations of Tigecycline.Our synthetic route has the characterof cheap raw materials, highyield and stable product quality and it is suitable for industrial production.