Synthesis Of Impurity Of Fludarabine(isomer) And Sildenafil(A&B)

In recent years,China has paid more and more attention to drug safety while keeping improving the drug approval system.Consequently,management of drug quality is becoming more and more important,and mastering accurate and comprehensive information of impurities of drugs plays a pivotal role.During the process of drug production and storage,some impurities may be generated which can affect the purity and quality of the drug directly or indirectly.Therefore,the quantitative and qualitative study of impurities of the drugs are highly indispensible in order to ensure the quality of the drug and the safety of the patient.The work in the present thesis mainly includes two parts.1.The first part of this thesis is focused on the synthesis of isomer impurity of Fludarabine(a new tumor suppressor),namely 9-(2,3,5-triacetyl-?-D-arabinofuranosyl)-2-fluoroadenine,to serve the quality control of Fludarabine as the impurity reference substance.Based on the literature survey,the synthetic route and condition of the isomer impurity have been explored and optimized,which begins with 2,3,5-tris-O-(phenylmethyl)-,1-(4-nitrobenzoate)followed by chlorination of anomer carbon,substitution with 2-fluoroadenine,removal of benzyl protecting group and acetylation to give the target impurity.2.The second part of this thesis is focused on the synthesis of two impurities of Sildenafil,namely,impurity A 5-{2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-1-methyl-3-(2-methyl-propyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and impurity B 5-{2-ethoxy-5-[(4-methyl-4-oxido-1-piperazinyl)sulfonyl]phenyl}-1,6-dihydro-l-methyl-3-pr opyl-7H-pyrazolo[4,3-d]pyriMidin-7-one}.According to the literature procedure,the literature synthetic conditions of sildenafil impurity A and B have been validated and further optimized.The problems associated with the literature synthetic process have been solved reasonably,and the reference substances of impurity A and B have been successfully prepared in multiple steps.All drug impurities synthesized in this thesis have been proved by MS,NMR,HPLC and IR to ensure meet the requirements of impurity reference substance.