Study On Green Oxidation Of Thioether And Its Application In The Synthesis Process Of Omeprazole

Sulfoxide and sulfone are important organosulfur compounds,which are widely used in medicine,pesticide,material,chemical industry,synthetic fiber and other fields.Traditional synthetic methods mostly employ the reaction of sulfonyl compounds with unsaturated bonds to generate sulfonyl groups in situ.However,these methods have low tolerance to functional groups and require severe reaction conditions.Thus,they are gradually replaced by thioether oxidation methods.Traditional thioether oxidation reactions usually use transition metals as catalysts,which may lead to environment pollution,and most of the reactions suffer from the low product selectivity.Therefore,exploring new thioether oxidation methods is a practical subject in pharmaceutical industry.The special crystal structure of cerium oxide can absorb more oxygen,which allows it to be used in a large number of catalytic oxidation reactions.The bonding between selenium and oxygen atoms gives it unique catalytic properties.As a kind of sulfoxide,omeprazole is also prepared by oxidation of thioether.The existing technique for synthesizing omeprazole has the disadvantages of high energy consumption,cumbersome operation and the like.In this thesis,we studies report the catalytic oxidation of sulfide to sulfone derivatives using cerium-or selenium-based catlysts.The technqiues are then successfully applied in the synthesis of omeprazole.The specific work contents are as follows:(1)In order to further expand the application of rare earth elements in organic chemistry,the Ce@TiO2 material was prepared by the sol-gel method after screening the matrix material and synthesis process.Through the screening of reaction conditions,the optimal reaction conditions were determined:acetonitrile was used as solvent,Ce@TiO2 was used as catalyst,1 equivalent of hydrogen peroxide was used as oxidant,and thioether was oxidized to sulfone at room temperature for 1 h.10 different substrates were successfully converted to the desired products in 70～89%yields.The morphology and structure of the catalyst were characterized by scanning electron microscope(SEM),high resolution transmission electron microscope(HRTEM),X-ray Diffraction(XRD)and other methods.It was also found that Ce@TiO2 was recyclable and this feature endows its application in industrial production.(2)Aiming at the problem that the sulfoxide product cannot be selectively obtained when cerium-containing materials catalyze the oxidation of sulfide,the catalytic system of organic selenium and metal ions was developed to improve the reaction selectivity.The reaction conditions were screened,and the best reaction conditions screened out.By using ethanol as solvent,benzene selenous acid and aluminum nitrate as catalyst and 1 equivalent of hydrogen peroxide as oxidant and performing the reaction at 25℃,sulfides were oxidized to sulfoxides selectively.Comparatively,by using 1 equivalent of hydrogen peroxide as oxidant and enhancing the reaction temperature to 40℃,sulfones could be successfully synthesized.Ten substrates were tested to provide the related products in 64%to 96%yields.The reaction mechanism was explored,indicating that the synergistic effect of Se,Al3+and NO3-was the key for the process.(3)The existing omeprazole synthesis process has the problems of cumbersome operation and high energy consumption.Therefore,based on the previous discussion on the seleniumcatalyzed thioether oxidation system,a new process for the synthesis of omeprazole was explored.After condition screening,the optimal reaction conditions were screened out.By using 1.25 equivalents of hydrogen peroxide as oxidant,the organoselenium-catalyzed oxidation in MeCN at 0℃ for 1 h could produce Omeprazole in 78%yield.According to the ultraviolet-visible spectrophotometry analysis result,the quality of the omeprazole product produced by this process complies with the latest national standard.