四极杆/静电场轨道阱高分辨质谱分析芬太尼类药物的裂解规律

Analysis of Fragmentation Rule of Fentanyl Drugs by Quadrupole/Electrostatic Field Orbitrap High Resolution Mass Spectrometry

采用四极杆/静电场轨道阱高分辨质谱仪,在分辨率高达70000情况下,直接采集碎裂片段的高精度质荷比(m/z),并通过元素模拟得到各碎片离子的元素组成,进而探究芬太尼类药物的裂解规律。结果表明:芬太尼类药物分子结构中叔胺基团的存在,使其极易被质子化,形成分子离子峰[M+H]^(+);裂解过程首先发生在叔胺与哌啶环相连的C-N键上,即哌啶环上的γ-H重排到与叔胺基团相连的羰基氧上,哌啶环上的β-键断裂(麦氏重排),形成一个中性丢失分子,另一端形成带电荷的碎裂片段,在高碰撞能量下,碎裂片段进一步发生裂解。按照化学结构将37种芬太尼类药物及其裂解途径划分为3类:(1)结构中含有N-苯基丙酰胺基团(149 Da),均可形成以149 Da为中性丢失的特征碎片离子m/z[M+H-149 Da]^(+);(2)N-苯基丙酰胺基团被其他任意非氢原子取代,而与之相连的哌啶环-苯乙基结构保持不变,中性丢失后则可产生特征碎片离子m/z 188.1433(C_(13)H_(18)N^(+)),随后哌啶环与苯乙基进一步发生N-C键断裂,形成特征碎片离子m/z 105.0702(C_(8)H_(9)^(+))和m/z 84.0814(C_(5)H_(10)N^(+));(3)不含完整母核结构的芬太尼类药物,多由修饰后的N-苯基酰胺与哌啶环构成,不能通过上述特征碎片离子进行定性,但均能通过高碰撞能量下吡啶环及其裂解产物m/z 84.0814(C_(5)H_(10)N^(+))和m/z 54.0724(C_(3)H_(4)N^(+))进行快速鉴定。

The quadrupole/electrostatic field orbitrap high resolution mass spectrometer was used to directly collect the high precision mass-to-charge ratio(m/z)of the fragment at resolution of 70000,and the elemental composition of each fragment ion was obtained through element simulation,so as to explore the fragmentation rule of fentanyl drugs.The results showed that the presence of tertiary amine group in the molecular structure of fentanyl drugs made it highly vulnerable to be protonated and formed molecular ion peak[M+H]~+.The fragmentation process firstly occured at the C-N bond of the tertiary amine connected to the piperidine ring,that wasγ-H from the piperidine ring rearranged onto the carbonyl oxygen attached to tertiary amine group,and theβ-bond from the piperidine ring broke(McGannell rearrangement),which formed the neutral-lost molecule and charged fragment at the other end,and the charged fragment was further broken off at high collision energy.The 37 fentanyl drugs and their fragmentation pathways were divided into 3 categories according to their chemical structures.(1)The structure contained the N-phenylacetamide group(149 Da),which could form characteristic fragment ion m/z[M+H-149 Da]~+after the compound neutral lost at 149 Da.(2)The N-phenylacetamide group was replaced by any other non-hydrogen atoms,while the associated piperidine ring-phenylethyl structure remained unchanged,and the compound neutral lost could produce characteristic fragment ion m/z 188.1433(C_(13)H_(18)N~+).Subsequently,the N-C bond between piperidine ring and phenylethyl was further broken to form the characteristic fragment ions m/z 105.0702(C_(8)H_(9)~+)and m/z 84.0814(C_(5)H_(10)N~+).(3)Fentanyl drugs without complete parent nucleus structure,mostly composed of modified N-phenylamide and piperidine ring,which could not be qualitative by the above characteristic fragment ions,but all could be quickly identified by the piperidinyl ring and its product ions m/z 84.0814(C_(5)H_(10)N~+)and m/z 54.0724(C_(3)H_(4)N~+).