Synthesis and Crystal Structure of The Potentially Genotoxic Impurity E of Avanafil
In the classical route of the synthesis of avanafil,the last step of the reaction uses EDCI and HOBT as an acid and amine binding agent.HOBT may contain residues of hydrazine,and potential mutagenic impurities containing acylhydrazide structures may be formed.The potentially genotoxic im-purity E(Imp-E)of avanafil,named(S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxym-ethyl)pyrrolidin-1-yl)pyrimidine-5-carbohydrazide,was synthesized by the reaction between the(S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxylic acid(M6)and the hydrazine sulfate,yield of 20％.The single crystal of Imp-E was cultivated by sol-vent volatilization method,and its structure was analyzed by high resolution mass spectrometry(HR-MS)and nuclear magnetic resonance spectroscopy(NMR).The Flack parameter of Imp-E was-0.03(3)by X-ray single crystal diffraction analysis,and the absolute configuration of Imp-E was deter-mined as S configuration.
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