Study On The Synthetic Process Of Halofuginone

Halofuginone is a derivative of febrifugine which was found in roots and leaves of the Chinese medicinal plant Dichroa febrifuga,which was originally synthesized in the late 1960s as a potential antimalarial agent.It has been on the market as a coccidiostat which was broad-spectrum efficient and low toxicity.Bsides,The research shows that the Halofuginone had great potencial activities on treating liver fibrosis and cancer,and the treatments of cGvHD,scleroderma,superficial bladder cancer and DMD are on the stage of clinical trial.Because of the complex process,it hasn't realized industrial production in China until now,and the price is high.The reports of total synthesis of halofuginone were rarer than febrifugine,through they both have the same Piperidinecarbonyl fragment,and it was the main and difficult points in the synthesis.The existing process conditions was achieved after the optimizing process of Baker's route.Based on this,In this study,we designed the route in which the Halofuginone was obtained from 2-acetylfuran by ring-expansion with ammonia,methylation,deprotonation,nucleophilic addition with acetonitrile,ketalation,hydrogenation catalyzed,and then hydrolysis,halogenation and acylation then condensation with 7-bromo-6-chloro-4-quinazolinone,hydrolysis.In this study we try to optimized the important reaction steps such as ring-expansion,methylation,halogenation,condensation and so on.The the overall yield was 24.78%after the optimization of the route,which is about 10%higher than the literature reports.At the same time,It validated the stability of process conditions of every step according small-sized continuous experiments and scale-up experiments,and designed the technological flowsheet,and to lay a foundation of pilot-plant test.The route has the advantage of higher yield,simpler work-upd and less environmental pollution.And the disadvantage is the use of n-BuLi as the deprotonation,that it will increase the cost and the intensity of labor protection and need to be improved.Even so,the Process also shows some significances on guiding industrial production.