High Stereoselectivity Manufacturing Process Development On Azacitidine

As China goes into aging society,the incidence of myelodysplastic syndrome?MDS?is increasing year by year,while the MDS treatment is difficult because of its obvious heterogeneity.Statistically about one third MDS die from complications related to bone marrow failure,and one third turn into acute leukemia,seriously threaten elderly health.MDS treatment mainly include supportive treatment,demethylation drugs,immunosuppressants and immunomodulating drugs.Studies have shown that MDS patients exhibits mutation-specific DNA methylation patterns,and demethylation drug Azacitidine has been the main research focus for MDS treatment in recent years.Azacitidine is the first demethylation drug shown to significantly prolong patient survival with moderate-2 and high-risk MDS and AML,significantly superior to traditional chemotherapy drugs.The efficacy is slightly better or equivalent to decitabine,better than 40%of other treatments.Myelodysplastic syndrome?MDS?and clinical diagnostic classification standard have been outlined in the paper,and the pathogenesis of myelodysplastic syndrome and the research progress of therapeutic drugs have been introduced,then the molecular genetics research of MDS,methylation mechanism,research overview and clinical efficacy have been summarized.The reasonable synthetic route of Azacitidine have been chosen in the paper after the theoretical analysis and practical attempt.In the route,?-D-ribofuranose was the starting material,and key intermediates V was obtained through acetalation,protection,hydrolysis and fluorination,then 5-azacytosine TMS-protected?I?was reacted with key intermediates V to obtain Azacitidine precursor V II through Vorbruggen reaction,which was then deprotected to obtain high-purity Azacitidine.In the process of preparing Azacitidine,the multi-step reaction conditions were investigated and optimized.Among them,due to the use of a fluorine leaving group and then catalyzed by boron trifluoride diethyl ether,the stereoselectivity of the reaction is high,the formation of a-isomer by-products is less,the content is only 1.8%,and the reaction conditions are mild,and the post-treatment operation is simplified.The yield of the Vorbruggen reaction is 78.2%,which is higher than current synthetic route;while use other leaving group reported in literature such as chlorine,bromine and acetyl,the yield is only 40-55%,and the alpha isomer content is 10-30%.After optimization,the total yield is 46.9%,and the purity is 99.89%.The structure of the target compound was confirmed by MS,¹H NMR and ¹³C NMR.