Study On Debenzylation/Debenzyloxycarbonyl By Catalytic Hydrogenation Methods

The process of protection and deprotection of functional groups is one of the important methods in chemical synthesis,and is especially of great significance in the synthesis of imipenem antibiotics.Meropenem was the first 1?-methyl carbapenem antibiotic used in medicine alone.It has been increasingly widely used in the treatment of severe and multiple drug-resistant infections and other fields.In this paper,aiming at the key technical problems,such as low selectivity,poor stability and other problems involved in the process of protection and deprotection of amino and carboxyl groups in the synthesis of meropenem,the reaction mechanismofprotectedmeropenemcatalysinghydrogenation debenzylation and debenzyloxycarbonylation was studied to speculate the catalytic mechanism of debenzylation and debenzyloxycarbonylation.On the basis of mechanism,catalysts and catalytic reaction system were scientifically modified and studied.The effects of the alkaline environment on the selective catalytic debenzylation and debenzyloxycarbonylation reaction were explored and palladium catalysts supported on mesoporous activated carbon with high stability and selectivity were prepared.It was found that the process of removing the carboxyl group was the rate-determining step and the alkaline environment can improve the selectivity of meropenem.The existence of organic bases added in reaction system can significantly improve the selectivity of the target product.It may be probably because the existence of organic bases promoted chemical dehydration inner molecule and suppressed the opening of four-membered ring thereby inhibiting C=C bonds hydrogenating and other side reactions.At the same time,the organic base provides a basic environment inclining to remove carboxyl group.In the process of modification of catalysts,catalysts with simple alkali metals doped,and activated carbons pretreated by bases and acids have all been studied,but none of these methods above is able to further improve the selectivity of the reaction.The selectivity and yield of the product were not increased by palladium catalysts doped with Cu or Fe.Based on the fact that alkaline environment was in favour of removing the carboxyl group,effects of the solvent on the reaction were investigated in the research.By changing the feeding mode in the reaction,the selectivity and yield were increased to 73.82%.Studies had shown that the solvent in the reaction may be moderate polar solvents.The total proportion of THF and H₂O,and the amount of the solvent had certain effects on the selectivity and yield in the hydrogenation reaction.When the total amount of the solvent was 145ml,of which THF was 64ml and H₂O was 81ml,the selectivity and yield of the reaction reached 84%.In the process of evaluation of the stability of catalysts,the structure and properties of the activated carbon had an effect on the stability of Pd/C catalysts on hydrogenatingdebenzylationanddebenzyloxycarbonylation.Pd/C catalysts supported on mesoporous activated carbon with narrow pore size distribution presented good catalytic activity and stability with the highest yield of 84.94%,and the recycling was also resolved.