Research On Synthesis Of Side Chain Of Ceftazidimeacid And Activated Thioester

Cefazidime is a very important third generation semi-synthesis cephalosporins.The upper products of ceftazidime such as ethyl (Z)-2-Hydroxyimino-2-(2-aminothiazol-4-yl)acetate，(Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonyprop-2-oxy imino) aceitc acid and2-(2-amino-4-thiazolyl)-(Z)-2-[(1-tert-butoxycarbonyl-1-methyl-ethoxy)-imino]acetic benzothiazolyl thioester，are not only the materials of preparingceftazidime but also the intermediates of preparing the forth generation cephalosporins. They have been widely applied in abroad and the prospect will be widelr.So thepreparation of upper products of ceftazidime was studied,and etherification reaction、hydrolysis reaction and esterification was optimized.Ethyl(Z)-2-(2-aminothiazol-4-yl)-2-(l-tert-butoxycarbonyl-l-methyl)ethoxyiminoacetate was synthesised by (Z)-2-hy droxyimino-2-hydroxyimino-2-(2-aminothiazol-4-) acetate and tert-Butyl-2-bromoisobutyrate under alkali condition. Thestudy was focus on alkali species,the amount of potassium carbonate, water, reactiontemperature, reaction time. The optimal reactive conditions were as follows:potassium carbonate as the reaction of acid binding agent, DMF as the solvent,molarratio of H2O、 potassium carbonate and (Z)-2-hy droxyimino-2-hydroxyimino-2-(2-amin othiazol-4-) acetate was1.2:2.46:1, recation time was1hunder60℃, and the reaction time was6hunder40-45℃. With these optimal reactiveconditions, the yield of Ethyl (Z)-2-(2-aminothiazol-4-yl)-2-(l-tert-butoxycarbonyl-l-methyl) ethoxyimino acetate was93.34%.(Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonyprop-2-oxyimino) aceitc acidwas synthesised by ethyl (Z)-2-(2-aminoth iazol-4-yl)-2-(l-t-butoxycarbonyl-l-methyl)ethoxyimino acetate by selective hydrolyzation under alkaline condition. The studywas focus on the kind of solvent, alkali species, alkali concentration, the ratio ofmethanol to water, the remaining amount of methanol, the acid types, different pH,temperation. The optimal reactive conditions were as follows: methanol and water assolvent, molar ratio of sodium hydroxide to ethyl (Z)-2-(2-aminoth iazol-4-yl)-2-(l-t-but oxycarbonyl-l-methyl) ethoxyimino acetate was1.3:1, methanol accounts for64%of the total mass of methanol and water, after the hydrolysis completing. Adjus-ting pH to7-8with hydrochloric acid. After recling methanol, adjusting pH to2.5-3 with hydrochloric acid or phosphate. With these optimal reactive conditions, the yieldof (Z)-2-(2-amino thiazol-4-yl)-2-(tert-butyoxycarbonyprop-2-oxyimino) aceitc acidwas80.03%.2-(2-amino-4-thiazolyl)-(Z)-2-[(1-tert-butoxycarbonyl-1-methyl-ethoxy)-imino]acetic benzothiazolyl thioester is prepared by (Z)-2-(2-aminothiazol-4-yl)-2-(tert-butyoxycarbonyprop-2-oxyimino) aceitc acid and DM under alkali condition. The studywas focus on the kind of solvent, the stability of the raw material and product, thecatalyst species, feeding method and so on. The optimal reactive conditions were asfollows: benzene–acetonitrile, triethylamine, pyridine as the base catalyst. Triethylphosphite dropwise3h diluted with acetonitrile. With these optimal reactiveconditions, the yield was91.03%.