苯甲酸阿格列汀的合成及其初步质量研究

Synthesis of alogliptin benzoate and its preliminary quality control

目的借助HPLC法对苯甲酸阿格列汀合成的各步中间体和产品进行质量控制,并对有关物质进行检测,优化其合成工艺路线,为工业化生产奠定基础。方法以6-氯-3-甲基尿嘧啶为起始原料,通过2次亲核取代、氯化氢乙酸乙酯脱Boc再与苯甲酸成盐,完成本品的合成。并对本品合成涉及的各步中间体、终产品及主要有关物质的HPLC检测方法进行优化,用于有效追踪合成过程和产品检测。结果本方法合成苯甲酸阿格列汀的总收率达52.6%～57.0%,纯度达99.5%,单杂均小于0.1%。结论改进后的合成工艺操作简便、反应条件温和,重现性好,更适合工业化生产。优化的HPLC方法专属性强、灵敏度高,可以有效监测产品质量。

Objective To improve the synthetic route of alogliptin benzoate, a reliable HPLC analytical method to control the quality of intermediates, and compounds for industrial production. Methods Alogliptin benzoate was synthesized as follows： starting from 6-chloro-3-methyl uracil, after 2 successive nucleophilic substitutions, removal of Boc group with hydrogen chloride in ethyl acetate, and salt formation with benzoic acid. HPLC was used to detect some materials including all chromatographs of the intermediates, products and related compounds. This method optimized the synthetic route of alogliptin benzoate. Results The product was synthesized at 52.6%- 57.0% total yield, with purity more than 99.5%, and any related impurity minimized to less than 0.1%. Conclusion The product meets the quality requirement of HPLC-detection. The improvement is simple with mild reaction conditions and good reproducibility, and is suitable for industrial production. The improved HPLC method is also specific and highly sensitive.