Study On Optimizatiom Of Synthttic Process And Quality Of Icotinib Hydrochloride

Icotinib Hydrochloride(trade name:Conmana)is a new targeted EGFR anti-NSCLC cancer drug,which is developed by Betta Pharmaceuticals Co.,Ltd through structure modification and activity screening on the basis of the chemical structure of Gefitinib(Iressa)and Erlotinib(Tarceva).Icotinib can treat the patients of NSCLC with EGFR mution,which is approved by the State Food and Drug Administration for listing in June 2011.Therefore,it will be a challenging and significant task to develop a new product with independent intellectual property rights and easy to realize industrial production.This dissertation has developed a fully novel process based on original process of Icotinib.Compound A was obtained through sulfonylation using triethylene glycol as substrate.Compound B was obtained using 3,4-dihydroxyphenylacetonitrile as substrate to construct 12-crown ether framework,which provided compound C through further nitration.Compound D was synthesized by catalytic hydrogenation in the presence of iron powder.Compound E was prepared by reaction with DMF-DMA and further reaction with 3-aminophenylacetylene,which afforded compound F.Finally,Icotinib hydrochloride was prepared by salt formation of hydrochloric acid.The toxic and harmful substances such as phosphorus oxychloride were discarded in the process,which made the production process more environmentally friendly and safety.The total yield of the reaction increases from 8% to 10% by comparision to the previous process,and the production cost decreases by 7%.Through quality research,the quality standards of starting materials and intermediates were established,and API quality standards and analytical methods were also established.The pilot scale-up production test was carried out,which laid a foundation for the industrialization of the new technics of Icotinib hydrochloride.