达托霉素新杂质及其来源研究

达托霉素是一种正在临床使用的新型抗耐药菌抗生素。由于结构特点,其具有很多结构类似的杂质。在达托霉素样品中,通过HPLC分析发现了一种新的杂质,相对保留时间为0.82。经过分离纯化,获得了纯化的新杂质。UPLC-MS检测发现新杂质的分子量为1617。核磁共振分析,确定新杂质的侧链含有双键,推定新杂质为N-(3-癸烯酰基)-L-色氨酰基-D-天冬酰胺酰基-L-天冬氨酰基-1-苏氨酰基-甘氨酰基-l-鸟氨酰基-L-天冬氨酰基-D-丙氨酰基-L-天冬氨酰基-甘氨酰基-D-丝氨酰基-苏-3甲基-l-谷氨酰基-L-3-邻氨基苯甲酰基-L-丙胺酸-ε1-内脂。根据杂质的化学结构,推测该杂质可能来源于发酵过程中补加的类酸。因此通过GC-MS分析了起始原料癸酸,发现其中含有少量癸烯酸,该结果证实了本研究的推测。

New impurity and source analysis of daptomycin

Daptomycin is a new antibiotic that is being used in clinic. Due to its structural characteristics, it has many impurities with similar structures. In the sample of daptomycin, a new impurity was found through HPLC analysis, with a relative retention time of 0.82. After separation and purification, a new impurity was obtained. The molecular weight of the new impurity was determined to be 1617 by UPLC-MS. The side chain of the new impurity was determined to contain a double bond by NMR analysis. The new impurity was confirmed as N-decenoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone. According to the chemical structure of the impurity, it was speculated that the impurity may be from decanoic acid added in the fermentation process. Thus the starting material, decanoic acid, was analyzed by GC-MS. A small amount of capric acid was found in decanoic acid. The result supported our