4-氨基烟酸的合成研究

Study on Synthesis of 4-Aminonicotinic Acid

4-氨基烟酸是合成心脑血管疾病治疗药物的关键中间体。今提出一条全新的4-氨基烟酸四步合成法,以起始原料异喹啉计算,总收率达30%。异喹啉氧化生成3,4-吡啶二甲酸,在乙酸酐作用下分子内脱水得3,4-吡啶二甲酸酐,酸酐氨解后经Hofmann重排反应引入C(4)氨基,完成目标分子4-氨基烟酸的合成;通过异喹啉氧化反应的对比实验,发现氧化剂硝酸-硫酸的性能明显优于高锰酸钾,反应收率提高到61%;优化了酸酐氨解和Hofmann重排的反应条件。该合成法起始原料价廉易得、操作安全、分离纯化简单,无需柱层析操作,最终产品纯度高,适合大规模制备。目标产物采用1H-NMR及IR进行了表征,其高性能液相色谱HPLC测得的纯度达98%。

4-Aminonicotinic acid is one of the key synthetic intermediates of therapeutic drugs for cardiovascular and cerebrovascular diseases.Here,a novel four-step synthesizing route of 4-aminonicotinic acid starting from isoquinoline was proposed,and its overall yield of 4-aminonicotinic acid can be up to 30%（based on isoquinoline）.During the preparation,the oxidation of isoquinoline gives 3,4-pyridine dicarboxylic acid,and after its intramolecular dehydration by acetic anhydride,the 3,4-pyridine dicarboxylic anhydride is formed.Then this anhydride is subjected to ammonolysis followed by Hofmann rearrangement reaction to introduce the C（4） amino group into the resulted nicotinic acid,and which leads to form the target product 4-aminonicotinic acid.The target product possessing 98% HPLC purity was characterized by 1H-NMR and IR.Based on comparative experiments,it was found that,as oxidant used in the isoquinoline oxidation process,HNO3-H2SO4 is prominently superior to KMnO4;and using HNO3-H2SO4,the yield can be improved up to 61%.The reaction conditions for anhydride ammonolysis and Hofmann rearrangement were optimized.The proposed synthetic technologies are suitable for large scale production,and their highlights include low cost and easy availability of starting material,safe operation,simple separation and purification,needless of chromatography operation and high purity of final product.