【摘要】 目的对琥珀酸曲格列汀的合成工艺进行系统研究,为其工艺放大奠定基础。方法以6-氯-3-甲基尿嘧啶为起始原料,通过2次亲核取代、氯化氢-甲醇溶液脱Boc,再与琥珀酸成盐制得琥珀酸曲格列汀。针对采用的特定路线,制备了5种主要有关物质的标准品。结果与结论选用(R)-3-Boc-氨基哌啶引入氨基侧链,可位置选择性地合成曲格列汀,4步反应的总收率达43.1%(以6-氯-3-甲基尿嘧啶计),终产物的纯度达到99.5%以上,单个杂质量均控制在0.1%以下。建立了琥珀酸曲格列汀合成所涉及的各步中间体、目标物及其有关物质的HPLC检测方法,并运用此方法进行合成过程控制及产品质量评价。更多还原

【Abstract】 Study on the synthesis of trelagliptin succinate was carried out systematically in this paper for the bulk synthesis. Starting from available 6-chloro-3-methyluracil and 2-cyano-5-fluorobenzyl bromide,the pro-duct was synthesized via two nucleophilic substitutions,removal of Boc protecting group and salt formation with succinic acid. The authentic samples of five possible related substances were also prepared for the sake of the quality-control study. A reliable HPLC analytical method was established here involving the intermediates,the product and main related substances of the route. This method was applied for the detection of the synthetic process and the quality-control of the intermediates and the final product.( R)-3-( Boc-amino)piperidine was employed in our selected route to regio-selectively construct the amino side chain of the final molecule. The synthesis proved to be practical for 4 steps in 43. 1%( based on 6-chloro-3-methyluracil)yield with more than 99. 5% purity,and any related substance was minimized to less than 0. 1% by HPLC analysis. The used conditions were well-tolerated.更多还原