Progress On Synthesis Of Efavirenz

Efavirenz is the non-nucleoside HIV-1 reverse transcriptase inhibitor anti HIV drugs, and it first appeared on the United States market in February 1999 by the Merck company research and development. For the characteristics of its effective therapeutic effect and favorable side profile in clinic, it has become one of the important varieties of drugs for AIDS therapy. There are the high cost and safety problems on preparation process of synthesis, so the study of its synthetic process for the variety development has an important value in our country.Efavirenz is a pure optical isomer, and its medicinal S isomer is used, but the corresponding R isomer almost non-existent biological activity. As present, there are a lot of literatures about synthetic study which have been reported and can be divided into two types: the one is asymmetric synthesis; the other one is chemical resolution.The study proceeded process improvement research which is based on the study of the Efavirenz chemical synthesis process in the early stage in our research group. The research work of two aspects is listd below:1. Using the S-(+)-mandelic acid to replace expensive resolving reagent R-(-)-camphanic acid chloride in the original process:We used the cheap resolving reagent S-(+)-mandelic acid for chemical resolution method exploration technology.In the process of chemical resolution, we selected the S-(+)-mandelic acyl chloride as resolving reagent which was preparated by S-(+)-mandelic acid, and combined with the Efavirenz raceme forming amide, and then hydrolyzed to get the product Efavirenz. Respectively, we investigated the material mole ratio, reaction temperature and other conductions on the resolution effect and to get the optimum resolution conditions was obtained as follows:(1) The first step: The preparation of acyl chloride. Acetyl chloride is used as acylating agent. The molar ratio of S-(+)-mandelic acid and acetyl chloride is 1:1.2.The molar ratio of S-(+)-acetoxyl phenylacetic acid and sulfoxide chloride is 1:1.8.Heating reflux reaction, and 3.5 h can response completely.(2) The second step: The preparation of amide. This is a key step response. The reaction conditions are: dichloromethane is used as reaction solvent, and the molar ratio of Efavirenz racemate: acyl chloride: triethylamine=1:1.6:1.5, and the mass-to-volume ratio of Efavirenz racemate and solvent dichloromethane is 1:25.Reaction temperature is 0 ℃, and reaction time is 3 h, and ethyl acetate/petroleum ether is dicided as an recrystallization solvent.(3) The third step: hydrolyzation. By optimizing, The solvent is N,N’-dimethyl formamide. The reaction temperature is 100 ℃. The mass-to-volumn ratio of amide and catalysis water is 1:1.6, and the mass-to-volume ratio of amide and solvent is 1:7.The reaction time is 4 h, and isopropyl alcohol/n-hexane is used to recrystallize product.The resolving method is cost cheap, simple post-processing, environmental friendly, high quality of the target, and the technology is relatively mature and suitable for industrial production.2. Using new reaction in the attempt to replace the original route of Grignard reaction: In order to avoid using Grignard reagent hidden trouble in security in the process of the industrial production, we try to adopt the method of the USA patent report that asymmetric synthesis techonology route to explore. The reaction used pyrrole alkyl-(L)-phenylpropanolamine as chiral auxiliaries, and it combined with zinc bromide, trifluoro ethanol and cyclopropyl acetylene magnesium chloride forming chiral organic zinc complexes under the effect of sodium hydride. Then it reacted with 2-trifluoroacetyl-4-chloro-aniline generating single isomers, and the last cyclization product target obitained Efavirenz. But after repeating response times according to the literature method we don’t get the target product, and get the removing group of trifluoromethyl by-product, and the by-product structure is confirmed by single crystal diffraction method. The reaction proves that the priority is to remove trifluoromethyl halide reaction under alkaline reaction conductions. So alternative Grignard reaction of type research still needs further exploration.All in all, according to the Efavirenz synthesis process improvement research, it has made obvirous progress, and confirms the reaction of the alkaline conditionwhich is preferred to generate side reaction products. After optimization, the over all reaction yield increases significantly, cost reduction, in saving raw materials, reaction time and various aspects have made great progress. The study provides a solid foundation for the large-scale preparation of Efavirenz.