盐酸鲁拉西酮的合成工艺优化及主要杂质研究

Improvement of synthesis process of lurasidone hydrochloride and research on its major impurities

目的:优化盐酸鲁拉西酮的合成工艺并对其工艺中的主要杂质进行研究分析。方法:以(1R,2R)-1,2-环己烷二甲醇为起始原料,经磺酰化、卤代、N-烷基化、取代、盐酸酸化5步制得盐酸鲁拉西酮,并对各步反应条件进行了优化;对盐酸鲁拉西酮的主要杂质进行合成,讨论其产生原因与控制方法。结果:总收率达63.1%[以(1R,2R)-1,2-环己烷二甲醇计],目标化合物及主要杂质均经EI-MS,~1H-NMR,^(13)C-NMR确证结构。结论:优化后的工艺收率高、步骤简洁、经济安全、适合工业化生产;杂质合成方法简便可行,为工业化标准制定和鲁拉西酮生产质控中杂质对照品的合成提供参考。

Objective： To optimize the synthesis process of lurasidone hydrochloride and study its major impurities. Methods： Lurasidone hydrochloride was synthesized by sulfonylation,halogenation,N-alkylation reaction,substitution and acidification,using（ 1 R,2 R）-cyclohexane-1,2-diyldimethanol as starting material and the reaction conditions of all steps were optimized. The major impurities of lurasidone hydrochloride were studied. Results： The yield was up to 63. 1% as calculated on（ 1 R,2 R）-cyclohexane-1,2-diyldimethanol. The structures of the objective product and the major impurities were confirmed by EI-MS,~1 H-NMR and ^（13） C-NMR. Conclusion：The improved process is easy to operate,and with high yield and economy,it is suitable for industrial production.The synthesis of the impurities is simple and can be provided as the reference substances for the synthesis of impurities and for the quality control of lurasidone hydrochloride.