Title (20) ESI HRMSn fragmentation payhways of some N-heterocyclic drug compounds . Introduction (120) The large amount of bibliography about EI mass spectra of organic compounds constitutes the support on which spectral databases were built. The huge diffusion of atmospheric pressure ionization methods does not correlate at present with a similar extent of work. The number of papers about gas phase fragmentation is not so large and sometimes useful pathways in spectral characterization look less known than simpler small molecules elimination reactions. In the current presentation some ESI multistage spectra will be shown in order to highlight slightly known fragmentation pathways. Ion trap vs. triple quadrupole behaviour will be shown and high resolution (Orbitrap) data will be used to confirm reaction hypotheses. A comparison with EI spectra will be included. Methods (120) HRMSn analysis were accomplished on a LTQ-Orbitrap instrument, with ESI interface coupled with a Dionex Ultimate 3000 LC system. Triple quadrupole experiments were run on a Varian 320-MS system. To elucidate some reaction mechanism, H/D exchange reactions were obtained by D2O solution or BuLi / D2O treatment. Gas phase proton affinity of different heteroatoms was calculated using the SPARC on-line calculator software. Preliminary data (300) Very different structures of drug molecules were considered: simple heterocycles (phenazone, nicotine), benzo-condensed (clonazepam, olanzapine) pyrimidino-condensed (caffeine, sildenafil), sulfonamides (sulfadiazine, sulfametazine). Interesting results emerge from the analysis of fragmentation behaviour of small molecules like phenazone (antipyrine). In this case, the lack of easy-to-eliminate substituents makes possible uncommon mechanisms: the loss of ammonia from the fully N-substituted molecule probably originates from hydrogen scrambling; the homolytic cleavage of the methyl group generate an intense ion and consequentely a series of odd-electron fragment ions. Also the losses of HCNO and CH3NH2 are noticeable. Some spectra are reminiscent of the corresponding EI ones: base peak of caffeine ESI HRMS2 spectrum is the product of a retro-Diels-Alder reaction. MS3 and MS4 characteristic fragment ions were useful in the identification of counterfeit analogues or metabolic derivatives (sildenafil, aminoclonazepam). Water inclusion in fragmentation pathways was evaluated in the case of sulphonamides. A scheme of the major neutral fragments observed is also presented. Novel aspects (20) Identification of fragmentation pathways of heterocyclic drug compounds useful to study unknown related substances.
ESI HRMSn fragmentation payhways of some N-heterocyclic drug compounds
MEDANA, Claudio
2010-01-01
Abstract
Title (20) ESI HRMSn fragmentation payhways of some N-heterocyclic drug compounds . Introduction (120) The large amount of bibliography about EI mass spectra of organic compounds constitutes the support on which spectral databases were built. The huge diffusion of atmospheric pressure ionization methods does not correlate at present with a similar extent of work. The number of papers about gas phase fragmentation is not so large and sometimes useful pathways in spectral characterization look less known than simpler small molecules elimination reactions. In the current presentation some ESI multistage spectra will be shown in order to highlight slightly known fragmentation pathways. Ion trap vs. triple quadrupole behaviour will be shown and high resolution (Orbitrap) data will be used to confirm reaction hypotheses. A comparison with EI spectra will be included. Methods (120) HRMSn analysis were accomplished on a LTQ-Orbitrap instrument, with ESI interface coupled with a Dionex Ultimate 3000 LC system. Triple quadrupole experiments were run on a Varian 320-MS system. To elucidate some reaction mechanism, H/D exchange reactions were obtained by D2O solution or BuLi / D2O treatment. Gas phase proton affinity of different heteroatoms was calculated using the SPARC on-line calculator software. Preliminary data (300) Very different structures of drug molecules were considered: simple heterocycles (phenazone, nicotine), benzo-condensed (clonazepam, olanzapine) pyrimidino-condensed (caffeine, sildenafil), sulfonamides (sulfadiazine, sulfametazine). Interesting results emerge from the analysis of fragmentation behaviour of small molecules like phenazone (antipyrine). In this case, the lack of easy-to-eliminate substituents makes possible uncommon mechanisms: the loss of ammonia from the fully N-substituted molecule probably originates from hydrogen scrambling; the homolytic cleavage of the methyl group generate an intense ion and consequentely a series of odd-electron fragment ions. Also the losses of HCNO and CH3NH2 are noticeable. Some spectra are reminiscent of the corresponding EI ones: base peak of caffeine ESI HRMS2 spectrum is the product of a retro-Diels-Alder reaction. MS3 and MS4 characteristic fragment ions were useful in the identification of counterfeit analogues or metabolic derivatives (sildenafil, aminoclonazepam). Water inclusion in fragmentation pathways was evaluated in the case of sulphonamides. A scheme of the major neutral fragments observed is also presented. Novel aspects (20) Identification of fragmentation pathways of heterocyclic drug compounds useful to study unknown related substances.
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