Improved Synthesis Of Nevirapine

Nevirapine is a non-nucleoside reverse transcriptase inhibitor for the treatment of AIDS. It is remarkably effective with few side effects.In this paper, we have reviewed anti-AIDS drug and syntheses of the commonly used drug in cocktail methods Nevirapine.Based on these, in order to create a novel industrialized synthetic procedure, a synthetic route which was less researched at home was designed according to industrialized basic requirements:using cyanoacetamide and ethyl acetoacetate as raw material by cyclization, chlorination, hydrolysis and Hofmann degradation, the key intermediate2,6-dichloro-4-methyl-3-amino pyridine was got; it was then condensed with2-chlorine chloride and cyclopropyl amine, cyclized in sodium hydride, catalyzed by hydrogenation to achieve Nevirapine. The synthetic route has made the reported syntheses better from the following four aspects:(1) it has simplified the tedious procedure of the hydrogen chloride and the selective chlorination;(2) it has been carried out under normal pressure and decreased temperature (115-120℃versus130℃reported in the literature) to use the pyridine and N, N methyl aniline as Fu acid agent.(3) toluene has been used instead of xylene for the reaction of bicyclic compounds and cyclic amines to reduce reaction temperature and time.(4) DMF and ethanol have been used instead of isopropyl alcohol for recrystallization in the refining process of Nevirapine to reduce the amount of solvents and improve the yield of crystallization. The synthesis route has generated intermediates via the simple workup without using highly toxic or polluting reagents.The product was confirmed by melting points. The structure of the key intermediate2,6-dichloro-4-methyl-3-amino pyridine was confirmed by1H-NMR. IR, UV,1H-NMR and other methods were used to prove the structure of Nevirapine correct.Quality research on Nevirapine was carried out. The reference substance and the sample were all analyzed by UV and IR. The results showed that the structure of the sample was in good agreement with the reference substance.The experiments were carried out three times. The experimental results showed that the yield and the quality were stable. It will be the foundation for the industrialized production.