The Synthesis Of VorieonazoLe And ?-CarboLine

This dissertation includes two chapters.Chapter one was the synthesis of voriconazole which was a new triazole derivative with broad-spectrum antifungal activity.In this chapter the mechanism of antimicrobial action and the progress on the synthesis of voriconazole were reviewed.At first methyl 2-fluoro-3-oxopentanoate was cyclised with formamidine acetate in the presence of NaOMe to give 6-ethyl-5-fluoro-4-hydroxypyrimidine,which was then chlorinated with POCl3 to afford 4-chloro-6-ethyl-5-fluor-opyrimidine(2).Then compound 2 was brominated with NBS afford 4-(1-brormoethyl)-2-chloro-5-fluoropyrimidine.The bromo-derivative of pyrimidine was then convertecd to their organiczinc derivates which undergoes nucleophilic addition to 1-(2,4-difluorophenyl)-2-(1 H-1,2,4-triazol-1-yl)-1-ethanone under Reformasky conditions to give(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(6-chloro-5-fluoro-4-pyriinidinyl)-1-(/H-1,2,4-triazol-1-yl)-2-butanol hydrochloride(6).Finally compound 6 under-go dechlorilation and resolution to give voriconazole with high purity.In this chapter the impurity profile of voriconazole was investigated and some impurities in voriconazole were also synthesized.The advantages of this process,such as mild reaction conditions,simple operation,high yield,make it attractive on large scale production of voriconazole in the future.The synthesis of a-carboline derivatives was studied.in second chapter.a-Carboline,a planar tricyclic N-heterocycle,.has demonstrated many biological activities,including anti-inflammatory,antianxiety and central nervous system stimulating activities.In this chapter we have successfully constructed a-carboline scaffold using 5-chloro-1,3-dihydro-2H-indol-2-one and vinamidinium salts as the raw materials.At first the nucleophilic reactions of 1,3-dihydro-2H-indol-2-one and vinamidinium-salts using triethylamine as base give 3-(3-amino-2-chloro-allylidene)-5-chloro-1,3-dihydro-Ind-ol-2-one,which was then cyclisezed to a-car-boline in 1,4-dioxane in the presence of phosphorus oxychloride.The effect of various reagents,solvents,temperature and substituent on the reaction yield was investigated.The plausible reaction mechanism was also proposed in this chapter.In conclusion we have developed a convenient and efficient method for the synthesis of a-carboline derivatives.