Cephalosporin Intermediate 3 - The Bit Structure Transformation Process Optimization Studies

Cephalosporin, which was exploitated in 1960s, has grown to the fourth generation and has taken possession of a half of antibiotics market in the last 50 years. As raw material of 7-ACA, the third position of it was modified, and cefotiam intermediate 7-ACMT and cefazolin intermediate TDA were synthesized. Synthetic processes of 7-ACMT were discussed and synthesis of 7-ACMT was optimized. A novel cephalosporin intermediate D-7-ACA was taken as research object to discuss its structure modification.7-ACMT which is an intermediate of cefotiam was synthesized by two ways: base catalyzed and boron trifluoride catalyzed. Preparation of 7-ACMT by base catalyzed was studied in this subject. As raw material of 7-ACA, the precipitation rate and effect of temperature on 7-ACMT quality were observed; the effects of halide salts and phase transfer catalysis on yields were observed; the differences of 7-ACMT quality between boron trifluoride method and base catalyzed were compared. The defect of poor product appearance on boron trifluoride method was avoided by using base catalyzed. An orthogonal experiment has been used for choosing the optimum conditions for synthesis of 7-ACMT in the method of base catalyzed. The optimum conditions are show below: the amount of 7-ACA 0.8 g, the amount of DMMT 0.57 g; the amount of chloroform 10 mL; the amount of water also 10 mL and the best reaction time 2 h.TDA which is an intermediate of cefotiam was synthesized by two ways: base catalyzed acid catalyzed (including boron trifluoride) catalyzed and organic silicon catalyzed. The method of base catalyzed will be studied in the subject. As raw material of 7-ACA, TDA was synthesized by the methods of ammonia water-water method, TEA-water method, ammonia water-buffer method, TEA-buffer method and TEA-acetone-water method. The pH value was stable and the reaction could be controlled because of the buffer. The purity of crude product rises from 90% to 98% with the help of acetone.Structure modification of the novel cephalosporin intermediate D-7-ACA in the third position was shown below: with the amino, carboxyl and hydroxyl of D-7-ACA protected by hexamethyldisilazane under the catalysis of chlorotrimethylsilane, the third position of D-7-ACA was tried to be iodated by trimethylsilyl iodide. Preparations of cefotiam intermediate 7-ACMT and cefazolin intermediate TDA were discussed as raw material of 7-ACA.