Synthesis Of Impurity Of Fludarabine G And Sildenafil(C&D)

Fludarabine(fludarabine)is a novel tumor suppressor with significant efficacy against B-cell chronic lymphocytic leukemia(CLL).Sildenafil(sildenafil)is the world's first oral medication for the treatment of erectile dysfunction(ED).However,some side reactions may produce some impurities during the process of production and storage of fludarabine and sildenafil.The existence of these impurities will directly or indirectly affect the quality of medicines,so a full mastery of the information of impurities in the drug can offer patients with safe and effective drugs.In order to ensure the quality of medicines and patients medication safety,it is necessary to conduct quantitative and qualitative studies of sildenafil and fludarabine impurities.1.The first part of this thesis is mainly directed toward the synthesis of an impurity that meets the quality control requirements of fludarabine,that is,the fludarabine G:(2S,5S)-5-(6-amino-9H-purin-9-yl)-4-chloro-3-hydroxytetrahydrofura n-2-yldihydrogen phosphate.Through thorough literature survey,the synthetic conditions of fludarabine impurity G were explored and optimized.The details are as follows.Beginning with fludarabine,the first step involves the protection of the hydroxyl group with 1,3-dichloro-1,1,3,3-tetraisopropyldimethoxysilane,the second step is to activate the hydroxyl group,the third step is the substitution reaction of lithium chloride,the fourth step is to use four n-butyl ammonium fluoride to remove hydroxyl protection,the fifth step phosphorylation reaction using phosphorus oxychloride.Finally,the product is obtained by preparation of HPLC.2.The second part of this thesis mainly focuses on the directional synthesis of two impurities that meet the quality control requirements of sildenafil,namely,sildenafil impurity C:5-(2-hydroxy-5-((4-methylpiperazine-1-ly)sulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,sildenafil impur ity D:4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyramid in-5-yl)benzene sulfonic acid.Through thorough literature survey,the synthetic conditions of sildenafil impurity were explored and optimized,the details are as follows.The synthesis of impurity C is based on sildenafil citrate as a starting material to obtain sildenafil under weakly alkaline conditions and then remove the ethyl under nitrogen protection.Impurity D is made by 5-(2-ethoxyphenyl)-1-m ethyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin sulfonated in concentrated sulfuric acid.The synthetic target compounds were finally confirmed by mass spectrometry,mass spectrometry,nuclear magnetic resonance,high performance liquid chromatography...