Study in the synthesis and crystal structure of the potentially genotoxic impurity E of Avanafil

Abstract

In the classical route of synthesizing 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 intermediate product (M6) of avanafil was synthesized by 6 steps using diethyl ethoxylmethylmalonate and S-methyl isothiourea semisulfide as starting materials. The potentially genotoxic impurity E (Imp-E) of avanafil was given by the reaction of M6 and hydrazine sulfate acid amine, yield of 20%. The single crystal of Imp-E was cultivated by solvent volatilization method, and its structure was analyzed by high resolution mass spectrometry (HRMS) 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 determined as S configuration. The intramolecular / intermolecular hydrogen bonds of Imp-E make the molecules maintain a stable arrangement in space.