Cephalosporins Intermediates 7-anca Synthesis Process Research

As members of the third-generation cephalosporins, ceftizoxime and ceftibu-ten demands are huge domestically. However, domestic companies have weak capabilities for their manufacturing and large amounts of them are dependent on import.7-Amino-3-nor-3-cephem-4-carboxylic acid (7-ANCA) is the key intermediate to ceftizoxime and ceftibuten. At present there is no large-scale production of 7-ANCA in China. The reason might be partially due to long reaction sequences and expensive reagents for all known synthetic schemes. Therefore, it is imperative to explore effective synthetic processes of 7-ANCA.By searching extensive literatures and studying the synthetic procedures reported previo usly, the synthetic route in this thesis is finally defined with part of the reaction steps are modified.7-ACA is taken as starting material and 7-ANCA is synthesized after steps of ami no protection, hydrolysis, carboxyl protection, oxidization, catalytic decarbonylation reaction a nd protection group removal.The main task of this thesis is to implement process optimizations for procedures includi ng amino protection, hydrolysis and carboxyl protection. For the amino protection procedure, we investigated the effects of molar ratio of precursors, pH and reaction time on the yield of 7-phenylacetamido-3-acetoxymethyl-3-cephem-2-carboxylic acid (compound 1) and got an optimized synthetic condition with the highest yield of 98.2%; for the hydroxylation and ca rboxyl protection, we researched the effects of molar ratio of precursors, pH, reaction time a nd amount of HCl solution on the yield of 7-phenylacetamido-3-hydroxymethyl-3-cephem-2-carboxylic acid diphenyl methyl ester (compound 2) and got itsoptimized synthetic condition with the highest yield of 81%.The key work of this thesis is studies on catalytic decarbonylation of diphenylmethyl 3-f ormyl-7β-phenylacetylamino-3-cephem-2-carboxylate. The catalytic decarbonylation of compoun dⅡwas studied using 5% (supported) composite catalysts prepared by common phosphine ligands and [IrCl(cod)]2 or RuCl2(cod). The results showed that the composite catalyst [IrCl (cod)]2/SBA-15/triethyl phosphite, among the investigated catalysts, exhibits the highest yield of 32% determined by HPLC and 23% after separation by chromatography, which is almost equal to the reported yield when stoichiometric amount of RhCl(PPh3)3 was employed as th e decarbonylation catalyst, and the composite catalyst can be recycled.The target compound was characterized by melting point,1H-and 13C-NMR analyses. F urther optimization and modification are still necessary to make the catalytic decarbonylation of diphenylmethyl 3-formyl-7β-phenylacetylamino-3-cephem-2-carboxylate.