Fragmentation pathways and differentiation of positional isomers of sorafenib and structural analogues by ESI‐IT‐MSⁿ and ESI‐Q‐TOF‐MS/MS coupled with DFT calculations

Abstract

Sorafenib is an orally active multikinase inhibitor for the treatment of renal cell carcinoma. A series of sorafenib structural analogues were investigated in this work for their gas-phase fragmentation behaviors using electrospray ionization ion trap mass spectrometry and quadrupole time-of-flight mass spectrometry in the positive mode. The possible fragmentation pathways were proposed based on ESI-MS/MS data and theoretical calculation. Different from the typical α-cleavage of amide, consecutive reactions that involved elimination of H₂ O and CH₃ NC were observed for 2-pyridinecarboxamide derivatives, which were followed by the formation of a stabilized 7-membered ring carbocation by loss of CO. Two possible protonation sites occurred at carbonyl oxygen atoms for aryl-urea derivatives and the α-cleavage of urea was the main fragmentation pathways, which was followed by the formation of stable benzo [d] oxazole ring characteristic to aryl-urea derivatives. The relative abundance of characteristic fragment ions and the energy-resolved breakdown curves were used to distinguish the 4 sets of positional isomers of sorafenib and analogues. The methodology and results of the present work would contribute to the chemical structure identification of other structural analogues and the potential impurities presented in active pharmaceutical ingredients and drug formulations.