Improvement Of Synthesis Process For Celecoxib And Its Analogs Synthesis

Non-steroidal anti-inflammatory drugs are clinically used in osteoarthritis,rheumatoid arthritis relieve various of fever and pain.Cyclooxygenase inhibitors are one kind of them.Celecoxib,which showed less side effects in clinical,was the first COX-2 specific inhibitors.In this thesis,the synthetic process of celecoxib was improved.Ethyl trifluoroacetate and methylacetophenone were used as raw materials,the compound 4,4,4-Trifluoro-l-(4-methylphenyl)-butane-1,3-dione was get by Claisen condensation reaction using the potassium carbonate as catalyst.The diketone compound reacts with 4-hydrazinophenylsulfonamide hydrochloride to obtain celecoxib.The total yield is higher as 85.5%.In two step synthesis,we analyzed and researched the main factor of the influencing reaction by single factor test and orthogonal experimental.The synthetic conditions of 4,4,4-Trifluoro-l-(4-methyl-phenyl)-butane-1,3-dione using the potassium carbonate as catalyst were optimized:under anhydrous system,the ratio of the reaction specials is lmmol p-methylacetophenone:3mmol ethyl trifluoroacetate:1.8mmol potassium carbonate,and the reaction yield is 95%for 48h.When "One pot" method was used to prepar celecoxib,the post-processing and drying steps in the preparation of the diketone intermediate were eliminated.The potassium carbonate was recycled after filter and calcine.The excess ethyl trifluoroacetate,reaction solvent in filtrate was recycled and reused by distillation.The synthesis process is cleaning greens,and suitable for industrial production.In order to improve cardiovascular side effects of celecoxib,according to the prodrug and twin principles of medicine,and based on ADMET predicted with Discovery studio,celecoxib analogs were designed and synthesized by the introduction of amino acid,dipeptide and tripeptide to sulfonamide amide group.The metabolites experiments in vitro shown the result were idential with the predication.