Study On Synthesis Of Tubercidin And The Synthetic Process Of Efavirenz

In this thesis,we mainly studied the synthesis of the nucleoside Tubercidin and the optimization of the synthetic process of the anti-HIV drug efavirenz.This thesis is divided into two parts:In the first part,based on introducing Tubercidin and other pyrrolo[2,3-d]pyrimidines compounds,the synthetic method of Tubercidin and the key intermediate 4-amino-7H-pyrrolo[2,3-d]pyrimidine was reviewed.In this thesis,4-amino-7H-pyrrole[2,3-d]pyrimidine was synthesized from malononitrile and bromoacetaldehyde diethyl acetal as starting materials by condensation,cyclization,thiol group oxidation,sulfinic hydrolysis removal,neutralization in 37.5%yield.the charge ratio of reagents and a variety of solvents for each reaction were screened.This synthetic method has some advantages such as cheap available material,mild reaction conditions,high yield,simple operation,which is suitable for the large-scale production.Furthermore the synthesis of nucleoside Tubercidin was developed from D-ribose as starting material through ketalization,hydroxyl protection,chlorination,condensation with 4-amino-7H-pyrrolo[2,3-d]pyrimidine.Then glycosidic bond was formed through Fisher-Helferich-Davoll method.In this thesis,4-amino-7H-pyrrolo[2,3-d]pyrimidine was fistly applied into the synthsis of Tubercidin,which will provide a novel route for the synthesis of nucleosides drugs.The second part briefly introduced the mechanism of action,pharmacological effects,pharmacokinetic parameter of anti-HIV drugs.The synthetic route of nonucleoside reverse transcriptase inhibitor efavirenz was also reviewed.(S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1-trifluorobut-3-yn-2-ol is the key intermediate of Efavirenz.In this thesis,the synthetic process of efavirenz was investigated in detail.The charge ratio,temperature and amounts of catalysts were.explored.The purification method for this key intermediate was developed,which could successfully fulfill the asymmetric synthesis of Efavirenz,the total in 82.9%total yield with up to 99%.Purity and 99%ee.