Process Optimization On Synthesis Of Side Chain Of Ceftazidime Acid And Activated Thioester

Cefazidime is a very important third generation semi-synthesis cephalosporins.Has a strong bactericidal and anti-bacterial broad spectrum of characteristics, beenwidely used in clinical. It is currently on the market the new and larger sales ofcephalosporins. Ethyl(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate,(Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonylprop-2-xoyimino)acetic acid,2-(2-amino-4-thiazolyl)-(Z)-2-[(1-tert-butoxycarbonyl-1-methyl-ethoxy)-imino]acetic acidbenzothiazolyl thioester. The upstream products limit the development of ceftazidimedrugs. Due to market competition, the cost of production is the bottleneck in thedevelopment of drug. Ethyl(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate,(Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonylprop-2-xoyimino)acetic acid,2-(2-amino-4-thiazolyl)-(Z)-2-[(1-tert-butoxycarbonyl-1-methyl-ethoxy)-imino] aceticacid benzothiazolyl thioester are not only the materials of preparing ceftazidime butalso the intermediates of preparing the forth generation cephalosporins. They havebeen widely applied in abroad and the prospect will be widelr. This thesis focuses onthe production process of the synthesis intermediates of ceftazidime were studied andimproved, including three sections:The first part is the improvement on the process of ceftazidime intermediate----Ethyl(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate, Ethyl acetoacetate asstarting material, with sodium nitrite under acidic conditions reacted to oximecompounds. The influence of different proportions and oximation reactiontemperature on the reaction yield and heterogeneous reactions was investigated. Afterbromination,cyelic condensation with thiourea. By comparing the experiments todetermine the synthesis conditions of the economy. And industrial production, theyield reached59%.The second part is on the process improvements of acid side chain of ceftazidime.Firstly,Ethyl(Z)-2-(2-aminothiazol-4-yl)-2-(l-tert-butoxycarbonyl-l-methyl)ethoxyimino acetate was synthesised by (Z)-2-hydroxyimino-2-hydroxyimino-2-(2-aminothiazol-4-)acetate and tert-Butyl-2-bromoisobutyrate under alkali condition.Secondly,(Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonyprop-2-oxyimino)aceitcacid was synthesised by ethyl(Z)-2-(2-aminothiazol-4-yl)-2-(l-t-butoxycarbonyl-l-methyl)ethoxyimino acetate by selective hydrolyzation under alkaline condition.Experimental study to optimize the reaction conditions; improve the yield. The yieldof the product exceeds the reported value.The third part is on ceftazidime activity thioester process improvement.2-(2-amino-4-thiazolyl)-(Z)-2-[(1-tert-butoxycarbonyl-1-methyl-ethoxy)-imino]aceticbenzothiazolyl thioester is prepared by (Z)-2-(2-aminothiazol-4-yl)-2-(tert-buty oxycarbonyprop-2-oxyimino) aceitc acid and DM under alkali condition. Used triethylphosphate instead of the expensive triphenylphosphine，Comparative experiment tooptimize the reaction conditions. Product yield of91.2%. And recycling the byproduct2-Mercaptobenzothiazole.2,2’-Dibenzothiazole disulfide was from the reaction ofoxidation to2-Mercaptobenzothiazole. The products were repeatedly appled andverificated, to fully meet the raw materials index. DM recovery rate of93.3%.