Study On The Structure Identification Of Impurities And The Mass Fragmentation Regularity Of Quinolinones

The present study was designed to identify the structures of the impurities in aripiprazole and cilostazol,and to summarize the mass fragmentation regularity of quinolinones,with aripiprazole and cilostazol as the model.First,compare the method for determining the related substances of aripiprazole in USP38,Ch P2015 and EP8.1 to establish suitable chromatographic conditions for mass spectrometric analysis.HPLC-Q-TOF combination technology was used to infer the structures of impurity 1,2 and X by obtaining MS and MS2 fragments.Based on the structures and the fragments,the mass fragmentation pathways of aripiprazole,impurity 1,2 and X were derived.In order to futher confirm the structure,impurity X was obtained by preparative HPLC,and identified by NMR,IR and UV that the structure of impurity X is 2,3-dichlorophenyl-piperazine-1-butane.The optimized chromatographic condition was verificated to be applicable for detecting impurity X.Then,compare the method for determining the related substances of cilostazol in USP36,Ch P2010 and JP16 to establish suitable chromatographic conditions for mass spectrometric analysis.HPLC-Q-TOF combination technology was used to obtain accurate molecular weight,and HPLC-Q-TRAP combination technology was used to obtain MS2 and MS3 fragments.The structures of eight impurities in cilostazol were characterized,four of which had not been reported previously,and the mass fragmentation pathways were derived.Last,we summarized that quinolinones drugs have 3 possible fragmentation regularities according to the electron donating ability of its two substituents,based on the 6 cleavage modes of the structure of the parent nucleus 2(1H)-quinolinones.1)The parent structure is easy to be broken into benzylic cation with amino group when the hydroxyl hydrogen in the seven position is replaced by a weak electron donating substituent,while there is no substituent on nitrogen.2)It is easy to form a relatively stable structure of positively charged benzene ring when the hydroxyl hydrogen in the 7 position is replaced by a strong electron donating substituent,while there is no substituent on nitrogen.3)When both of them are strong electron donating substituents,the parent structure is easy to occur the beta break of carbonyl carbon and form benzyl positive ion.