Study On Synthesis Of Efavirenz As The Anti-aids Drug

Efavirenz is a non-nucleoside reverse-transcriptase inhibitor(NNRTIs)of anti-AIDS drugs and has been used in combination with other antiretrovirals for the treatment of HIV infection.It has many good points such as long half-life,well tolerance,good treatment effect,minor toxic side effect,etc.There are two kinds for the synthesis of Efavirenz: one is chemical resolution and the other is asymmetric synthesis.In this paper,we choose the asymmetric synthesis method for preparing Efavirenz.Using 2-trifluoroacetyl-4-chloro aniline as the starting material,the process has been carried out in 5 steps including preparation of Grignard reagent,asymmetric synthesis,amidization,cyclization and purification.we have established a synthetic route which is suitable for industrialized preparing of Efavirenz(overall yield 81.5%,99.96% purity and 99.9% ee).Both product quality and yield are better than current level technology(overall yield 69.6%,99.5% purity and 99.5% ee).The main research work of three aspects and the relevant results are listed below:(1)We choose the method of asymmetric synthesis to prepare(S)-1-(2-amino-5-chlorophenyl)-1-(trifluoromethyl)-3-cyclopropyl-2-propyn-1-ol which is the key intermediate of Efavirenz.Using the chiral ligand(1R,2S)-1-phenyl-2-pyrrolidino-1-propanol as the catalyst and in the presence of sodium hydride,2,2,2-trifluoroethanol,zinc chloride and a solution of chloromagnesium-cyclopylacetylide,the target compound has been prepared(yield 91.8%,99.7% purity,99.98% ee).(2)Using the methyl chlorofomate as the cyclization reagent,one-pot synthesis method has been carried out through three steps such as amidization reaction(without acid acceptor),reflux dewatering(with toluene)and cyclization reaction(with t-BuOK)to get the Efavirenz(92.5% yield,99.96% purity and 99.9% ee).(3)At last,we have studied the crystal forms of Efavirenz corresponding to the different crystallization conditions.Finally,the mixture of ethanol-water has been choosed as the crystal-solvent for obtaining a stable crystal form I of Efavirenz(yield over 96%).In this paper,by consulting a lot of literatures and enough experimental verification,a high efficiency and easy operation processes for the preparation of Efavirenz has been established,and provides a good technological foundation for the industrialization of this product.