Synthesis Of Voriconazole Intermediates And Their Process Optimization

Voriconazole is a second-generation triazole antifungal drug obtained by modifying early fluconazole,which has the characteristics of broad antibacterial spectrum,strong antibacterial efficacy and good safety.The drug was developed by Pfizer and first marketed in the United States in 2002.Clinically,it is mainly used for the treatment of acute or chronic deep fungal infections.Since nearly 5 million people worldwide lose their lives due to fungal infections every year,the demand for antifungal drugs in the domestic market is growing rapidly and the market potential is huge.Therefore,it is necessary to optimize the synthesis of voriconazole intermediates to make them more conducive to industrial production and have good economic benefits.In this paper,the voriconazole route reported in the literature was analyzed,and on the basis of summarizing the literature,the reaction types,reaction difficulty,environmental protection,industrialization,production cost,yield and other aspects of different routes were compared,and a route of industrial production with"6-（1-bromoethyl）-4-chloro-5-fluorouracil as the key intermediate"was selected.The key intermediates of Voriconazole were synthesized from relatively cheap ethyl fluoroacetate by nucleophilic substitution,cyclation,chlorination and bromination,and the four-step reaction conditions were optimized systematically.The study is as follows:1.The key bromine intermediates of Voriconazole were synthesized and their structures were confirmed by hydrogen,mass and carbon spectra.2.The selection of solvent,reaction equivalent,reaction temperature,reaction time,the amount of solvent,the formation of impurities and so on in each step of the reaction were systematically studied to determine the optimal process conditions of each step of the reaction,which improved the yield and greatly reduced the production cost.（1）The optimum conditions for the synthesis of ethyl fluoropropionyl acetate were determined as n_{（ethyl fluoroacetate）}:n_{（propionyl chloride）}:n_{（sodium ethanol）}=1:1:5:2.The optimal solvent was n-hexane and the preferred temperature was 50℃.（2）The best synthesis process of 4-hydroxy-5-fluoro-6-ethylpyrimidine was determined to be n（ethyl fluoropropionyl acetate）:n（formamidine acetate）:n（sodium methanol）=1:1:3,the best reaction time was 5 h,and the post-treatment method was concentrated solution p H adjusted to 5,drop to the water solution,crystallization solvent choice of isopropyl alcohol is the best.（3）The optimum conditions for the synthesis of 4-chloro-6-ethyl-5-fluorouracil were determined as n（4-hydroxy-5-fluoro-6-ethylacil）:n（phosphorus trichloride）:n（triethylamine）=1:1.3:1.1.From the screening of solvents,dichloromethane was the best,and the best reaction time was 5 h.（4）The optimum conditions for the synthesis of 6-（1-bromoethyl）-4-chloro-5-fluorouracil were determined as n_{（4-chloro-6-ethyl-5-fluorouracil）}:n_（NBS）:n_（AIBN）=1:3:0.05,the optimum solvent was selected for acetonitrile,the optimum reaction temperature was 80℃,and the optimum reaction time was 6-8 h.