The Synthetic Study Of Nevirapine

Nevirapine, the first non-nucleoside reverse transcriptase inhibitor, was lunched in 1996 in America. It is widely applied for the treatment of AIDS disorders, especially for the blockage of vertical transcription of the HIV from mother to infant.The development of AIDS disease, the pathogenic mechanisms of HIV and the research progress of the anti-AIDS drugs were reviewed in the thesis; The different aspects of Nevirapine such as the pharmacology and the pharmacokinetics also introduced here.Starting from methyl formate and acetone, the key intermediate,2-chloro-3-amino-4-methylpyridine(9, CAPIC) was prepared via five steps such as the Knoevenagel condensation, cyclization, chlorination, the cyano-hydrolysis, and the Hoffmann degradation. Then it was condensed with 2-Chloronicotinoylchloride(10) to give the 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide(11) which was aminolyzed by cyclopropylamine in an autoclave and followed by the intramolecular nucleophilic substitution to give the target compound(1) with a total yield of 15.1% from acetone.In this paper, anhydrous MgSO4 was used as dehydrating agent to accelerate the Knoevenagel reaction. The product obtained was brought to the intramolecular condensation to give the 3-cyano-4-methyl-2-pyridone(6) in the presence of p-TsOH as a catalyst in this thesis. During the preparation of the amide 11, CH2Cl2 was used as the solvent to replace the dangerous and toxic mixture of cyclohexane-dioxane reported in literatures, and pyridine was employed as the base instead of N,N-dimethylaniline or potassium carbonate. This easily operated and much safer process could also improve the yield of the reaction. Moreover, potassium t-butoxide was employed for the last step in this paper to avoid the use of the dangerous NaH or expensive NaHMDS.