Synthetic Process Research Of Anticancer Drug Substance Of Erlotinib Hydrochloride

Erlotinib hydrochloride is a kind of 4-phenylamino quinazoline small molecular compound,which was developed by Roche and Genentech Pharmaceutical companies.It is a anti-tumor drug with protein tyrosine kinases as targets and it is used for the treatment of non-small cell lung cancer and pancreatic cancer.Due to its excellent anti-tumor activity and huge market share,Erlotinib hydrochloride has got extensive attention since 2004.The existing synthetic methods reported in literatures have disadvantages such as unfriendly environmental,too many byproducts and lower yields etc.So it is meaningful to develop Erlotinib hydrochloride synthetic process with higher yield,lower cost and easy industrialization.In this thesis,based on the synthetic route in the literature,Erlotinib hydrochloride is synthesized from ethyl 3,4-dihydroxybenzoate and 2-chloromethoxyethane followed with nitration reaction and nitro group reduction to get ethyl 2-amino-4,5-bis?2-methoxyethoxy?benzoate.After that,the ring closing reaction is proceed by ammonium formate and formyl amide to get quinazoline derivatives.Then quinazolin intermediate is chlorinated by thionyl chloride and finally reacted with 3-ethynylphenylamine to get Erlotinib hydrochloride.According to the concept of QbD?quality by design?,during each step,the critical process parameters such as raw materials ratio,temperature and reaction time are optimized to get more commercialized process with high yield.And the process stability is investigated.Another work in this thesis is to set up the high performance liquid chromatography method for monitoring each reaction and controlling intermediate quality.Head Space-GC method is developed to monitor residue solvents of Erlotinib hydrochloride to meet the international drug registration requirement.The structure of Erlotinib hydrochloride is confirmed by ¹³C-NMR,¹H-NMR,MS and FTIR.