A Study On The Synthese Of The Impurities In TKI Neratinib And A Novel Synthetic Technology Of Cholagogic Dyskinebyl

In this paper, the impurities of Neratinib、cholagogic Dyskinebyl and their synthetic methods were studied, which consists of the following two parts。Part Ⅰ:The study on the synthetic methods of impurities in the NeratinibNeratinib, a new kind of orally available, irreversible Pan-ErbB receptor tyrosine kinase inhibitor, was developed firstly by wyeth pharmaceutical co. LTD. Neratinib can inhibit the bioactivity of ErbB-1 and ErbB-2 tyrosine kinase effectively, and has been researching in a Phase Ⅲ clinical trials. The degradation products and process impurities are the main impurities of Neratinib, and there were 11 compounds have been reported. Targeting the 11 compounds, this paper designed their synthetic routes through literature investigation. At the first, we prepared impurity B from N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and 3-chloro-4-(pyridin-2-ylmethoxy)aniline. Then we synthesized these 11 compounds successfully through the modifications on C6-NH2 of impurity B. The 11 compounds were determined and identified by ESI-MS, 1H-NMR and 13C-NMR.Part II:The novel synthetic method of cholagogic DyskinebylDyskinebyl is referred to "a really efficient and ideal cholagogue", which was developed and marketed by Laphal Laboratories successfully. It’s main active ingredient is dihydroxydibutylether. We synthesized Dyskinebyl through Grignard reaction, Williamson reaction, epoxidation reaction and reduction ring-opening reaction from 3-chloropropene. characterized with simple synthetic route and cheap raw material. The total yield is 35% and the structures of intermediates and target compound were determined and identified by 1H-NMR and 13C-NMR.