The New Process For Synthesis Of Cefquinome Sulfate And Development Of Long-acting Cefquinome Sulfate Injection

Cefquinome sulfate is the forth generation cephalosporin antibiotics special for veterinary. It is a broad-spectrum and high effective cephalosporins antibiotics, have the broader antibacterial spectrum and stronger bactericidal effect than the third generation cephalosporin. The intrinsic antibiotic activity of Cefquinome is stronger than the previous three generation cephalosporins. Compared with the previous three generation cephalosporins, the dosage of Cefquinome sulfate is smaller. The forth generation cephalosporin have more sensitive on treatment of bacteria, a longer plasma half-life and no renal toxicity.This thesis is based on the further study of all relevant literatures, and comprehensivly considerate about the basic requirements of industrialization. This paper describes a new method for synthesis of cefquinome sulfate, which take GCLE as the starting material. After the chlorine in chlorine methyl at C-3position is substituted with iodine, it reacte with hydrogen,5,6,7,8-four quinoline, then get the intermediate7. In the reaction with phosphorus pentachloride and phenol, remove the C-7amino group protection and C-4carboxyl group protection, and react with AE-active ester under Triethylamine system, finally get the target product--Cefquinome Sulfate.This new synthesis method can effectively solve the several issue of the original process. The reaction condition of original one is harsh, the reaction system is complex, it is difficult to be separated and purified, and the purity of the product and color are not good. This new synthesis route is more simple, have mild reaction conditions, the yield is higher, the coster is lower, and the price of raw materials is cheap, easy to be souced. The new route is more suitable for scaling up. Combined with the micro imaging technology and high performance liquid chromatography, this thesis study the crystallization process. Adding seed crystal of product and shorten the crystallization time is good to improve the purity of the products. Crystal seed is conducive to the growth of crystal in the longitudinal direction, and most of the crystal is rod. The product has good stability of quality. Use the FT-IR and NMR to characterize the final products, test results show that the obtained product is cefquinome sulfate.Currently cefquinome sulfate injection effect a short time in human body. To reduce animal stress response and frequency of drug use, this paper studies the cefquinome sulfate injection. Through the orthogonal design method, screen out the best prescription of cefquinome sulfate injection. Finally get the cefquinome sulfate injection which is more stable and have more reliable long-term therapeutic effective. After the study of process technology, the pilot experiment results show that, the long-acting cefquinome sulfate injection from new synthetic route meets the quality specification. After a stability study of18months, the quality of this product have no significant change, the quality stability is very good.