维生素E中间体三甲基氢醌合成工艺中有关物质的制备及结构鉴定

目的：对合成维生素E重要中间体三甲基氢醌工艺中所含的2个主要未知杂质进行结构解析。方法：采用等度洗脱高效液相色谱分析方法确定三甲基氢醌的杂质谱；通过两次半制备色谱方法及梯度洗脱分离出未知杂质1和杂质3；非挥发性目标物洗脱液浓缩采用减压旋转蒸发方法，挥发性目标物洗脱物采用固相萃取分离技术。杂质的精确分子量由高分辨质谱测定；杂质化学结构式采用高分辨一维和二维核磁共振谱进行结构解析。结果：两未知杂质经结构鉴定为2，5-二甲基氢醌和2，3，5-三甲基-2-环已烯-1，4-二酮，后者为首次报道。结论：本研究为易挥发性化学药物的有关物质结构解析提供了思路。

Objective: To evaluate and identify two major process-related impurities from bulk synthetic trimethylhydroquinone(TMHQ)-a critical intermediate which is widely applied in synthesis of vitamin E acetate.Methods: The impurities profile was analyzed by HPLC with isocratic solvent elution. The two major processrelated impurities were separated twice by semi-preparative liquid chromatography with gradient solvent elution. The enrichments of target elution were performed with vacuum rotary evaporator for nonvolatile ingredient and solid phase extraction technology for volatile ingredient. The exact molecular weight of two processrelated impurities were measured by high resolution mass spectrometry. The accurate chemical structures were characterized by high resolution nuclear magnetic resonance(NMR)with one dimensional ¹H, ¹³C, DEPT-135 spectra and two dimensional H-H COSY, H-C HSQC and H-H NOESY spectra.Results: Two process-related impurities were identified as 2,5-Dimethylquinone and 2,3, 5-trimethyl-2-cyclohexene-1,4-diketone, which has not been reported to the best our knowledge.Conclusion: The present study provides a better method for structure elucidation of volatile impurities which are difficult to be prepared.