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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。
Objective To systematically study the synthetic process of troxytin succinate and lay the foundation for its process amplification. Methods The 6-chloro-3-methyluracil was used as the starting material, and substituted with 2 nucleophilic nucleophilic substitutions and hydrogen chloride-methanol solution to desorb Boc and then succinate. For the specific route used, five major standards of related substances were prepared. RESULTS AND CONCLUSIONS The introduction of (R) -3-Boc-aminopiperidine into the side chain of amino group led to the selective synthesis of treprostinil. The total yield of 4-step reaction was 43.1% (using 6-chloro-3- Uracil), the purity of the final product reached more than 99.5%, the amount of individual impurities are controlled below 0.1%. The HPLC method for the determination of intermediates, targets and their related substances involved in the synthesis of troxerotropine succinate was established and used to control the synthesis process and evaluate the product quality.