磷酸西格列汀制剂中有关物质的合成

Synthesis of Sitagliptin Related Substances in Sitagliptin Phosphate Tablets preparations

摘要:

摘要：以西格列汀为原料依次富马酸二甲酯和马来酸酐分别经氮杂迈克尔加成和胺化反应制备相应西格列汀有关物质：①以西格列汀和富马酸二甲酯为原料，在DBU催化剂作用下，在N2保护下25℃搅拌6小时，经氢氧化锂，用乙酸乙酯-盐酸调节pH后，水相析晶体系分离提纯，得到西格列汀加合物有关物质I，HPLC纯度大于99%，收率76%；②以马来酸酐为原料，在K2CO3催化作用下，室温搅拌2小时，经一步法胺解开环反应制备西格列汀有关物质II，收率97%。本方法路线短，能耗低，生产成本低，操作简单，两种西格列汀有关物质收率好纯度高，适合工业化生产。

Abstract:

Abstract: The preparation of sitagliptin related substances by the aza-Michael addition reaction of dime-thyl-maleate or maleic acid to sitagliptin is crucial to assist in research of the risk control of sitagliptin drug impurities：①Using sitagliptin and dimethyl fumarate as raw materials, 1,8-Diazabicyclo（5.4.0）undec-7-ene (DBU) as a catalyst, stirring at 25?C for 6 hours under N2 protection, separation and purifi-cation by Ethyl Acetate - HCl - H2O crystallization system, 76 % yield of the sitagliptin impurity I, 99% purity by HPLC; ②Maleic acid as raw material, stirring at room temperature for 2 hours with K2CO3, to prepare sitagliptin impurity II by one-step method, up to 98% yield. The two kinds of sitagliptin impurities have been synthesized with good yield and high purity, and has the advantages of short route, low energy consumption, low production cost and simple operation for industrial production.