Research On Synthesis Of Side Chain Of Ceftazidime Acid And Activated Thioester

Ceftazidime is an important third generation semi-synthesis cephalosponns. Because it exhibits broad antibacterial spectrum and strong antibacterial activity, it is applied widely to clinic , and sold well in market. In industy, the upper products of ceftazidime limit the development. Thyl (Z)-2-Hydroxyimino-2-(2-aminothiazol-4-yl)acetate (iv), (Z)-2-(2-amin -othiazol-4-yl)-2-(tert-butyoxycar-bonylprop-2-oxyimino)acetic acid( vii) and 2-(2- amino-4-thiazolyl)-(Z)-2-[(l-tert-butoxycarbonyl-l-methyl- ethox y)-imino]acetic acid benzothiazolyl thioester (viii) are not only the materials of preparing ceftazidime but also the intermediates of preparing the forth generat-ion cephalosporins. They have been widely applied in abroad, and the prospect will be wider.Some improvements of synthetic methods about intermediates of Ceftazidime are researcheded. The article is divided to three parts to describe.(1) The synthesis of thyl(Z)-2-hydroxyimino-2-(2-aminothiazo l-4-yl)acetate(iv) is discussed. It is not only an important intermediate of Ceftazidime but also an essential material of other cephalosporins.Compound(iv) was prepared from the first materials Ethyl acetoacetate ( i ) via oxidation in the presense of NaNO2 under the acid condition, bromination ,cyclic condensation with thiourea. The influence of different mixture solvent and the volume ratio of methyl alcohol and water on the yield is investigated. Through orthogonal design experiment, the suitable synthetic condition is determined. The structure is confirmed by JHNMR, and the melt point of the product conforms to that in reported document. Its total yield is up to 56.2%.(2) The synthesis of(Z)-2-(2-aminothiazol-4-yl)-2-(tert.-butyoxy carbonylprop-2-oxyimino)acetic acid(vii) is researched. Compound(vii) is prepared by two steps, firstly, thyl(Z)-2-Hydroxyimino-2-(2-aminothiazol -4-yl)acetate(iv)reacts with compound (v)to produce compound (vi). Secondly , compound(vii)is obtained from compound(vi) by selective hydrolyzation under the alkaline condition.Through orthogonal design and uniform design , the reaction conditions were optimized to improve yields. In this study the after_work_up methods about compound (vii) are improved, and the purpose product with high yield and high quality is obtained. The structure was confirmed by ^NMR, and the melt point of the products conform to those of reported document. The yield exceeds that reported in the domestic relevant documents.(3) The synthesis of 2-(2-amino-4-thiazolyl)-(Z)-2-[(l-tert-butoxycarbonyl-l-methyl-ethoxy)-imino]acetic acid benzothiazolyl thioester (vi) is researched . There are few document about the synthesis of compound (vii). In alkali condition, condensate (Z)-2-(2-aminothiazol-4-yl) -2-(tert.-butyoxycarbonylprop-2-oxyimino)acetic acid (vii) with DM in presnse of Triethyl phosphate to form intermediate(viii). Used triethyl phosphate instead of the expensive Triphenylphosphine, solventacetonitrice instead ofthe mixture of 2-dichloromethane and water, the reaction can be carried out succefully. The reaction conditions are optimized to improve yield by orthogonal design experiment. The melt point of the product and 1HNMR conform to those in document reported. The yield of the product is up to 86.8%.