Study On The Synthetic Process Of Efavirenz

Efavirenz is a non-nucleoside reverse transcriptase inhibitor recommended by the World Health Organization.It plays a critical role in anti-HIV therapy due to its better tolerability and less side effects.In this thesis,two plausible synthetic routes of efavirenz were designed,experimentally verified and optimized.Details are described as follows:The first chapter introduced the pathogenesis and therapeutic status of AIDS as well as current research progress towards anti-AIDS drugs.The profiles of efavirenz was also introduced,including structure-activity relationship,pharmacokinetic,clinical efficacy and side effects.In addition,various approaches to the synthesis of efavirenz were described in detail,which provided the theoretical support for putting forward the research.The second chapter designed two synthetic routes of efavirenz viaretrosynthetic analysis,starting from 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate 32.Route I: upon the treatment of 32 with base,the corresponding aniline 6 was obtained for the p-methoxybenzyl protection.The asymmetric addition of p-methoxybenzyl-protected ketoaniline 17 mediated by chiral ligands afforded the intermediate 19,which was then deprotected to give the compound 22.Efavirenz was finally obtained by ring-closure of 22.Route II: through the protection and chiral induction with S-naproxen,efavirenz was obtained via asymmetric addition,followed by deprotection and ring-closure.Experimental results indicated that route I was feasible and the desired product was obtained in five steps with an overall yield of 63% while route II was not effective.In summary,the preferred synthetic route of efavirenz is described as follows: treatment of hydrochloride hydrate 32 with base provided the corresponding aniline 6,which reacted with p-methoxybenzyl alcohol catalyzed by p-toluenesulfonic acid to obtain the protected product 17 in total yield of 89%.Through the asymmetric addition mediated by(1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol,the intermediate 19 was obtained in 83% yield with 99.7% ee.The deprotection product 22 was obtained in 86% yield after oxidation with DDQ and treatment of p-toluenesulfonylhydrazide.The target compound efavirenz was synthesized by ring-closure of 22 in 98% yield with 99.9% ee.Thismethod has many advantages such as accessible raw materials,mild reaction conditions and excellent optical purity.