氟化钾促进的尼替西农原料药的合成

Synthesis of nitisinone drug substance promoted by potassium fluoride

本文报道了一种尼替西农合成的新方法。以2-硝基-4-三氟甲基苯甲酸为起始原料,先与氯化亚砜反应制成酰氯衍生物后,在无水氟化钾参与下,与1,3-环己二酮缩合得到尼替西农粗品,经重结晶纯化终产品总收率63%、纯度>99.5%。氟化钾的使用,可有效降低烯醇酯异构体杂质的生成,提高反应的选择性和底物转化率,同时避免了使用剧毒、高污染的氰基化试剂,具有较为绿色安全的优点。

A new method of synthesis of nitisinone was reported in this paper.With 2-nitro-4-trifluoromethylbenzoic acid as the start-ing material,acyl chloride derivative was prepared by reacting with thionyl chloride,and then condensed directly with 1,3-cyclohex-anedione in the presence of anhydrous potassium fluoride to obtain the crude Nitisinone.Finally,after recrystallization and purifica-tion,the total yield of the final product was 63%and purity>99.5%.The use of potassium fluoride could effectively reduce the gen-eration of the enol ester isomer impurity,improve the selectivity of the reaction and substrate conversion,and avoid the use of highly-toxic and highly polluting cyanidation reagents,which had the advantages of green chemistry and safe production.