Synthesis And Synthetic Optimization For Erlotinib Hydrochloride

In recent twenty years, there has heen a growing tendency of cancer incidence. Prevention and treatment of cancer have been attracting immense interest among pharmaceutical industry.The mechanism of tumor have been clarified with the development of oncology and related disciplines, and anti-tumor research focused on the regulation of cell signal transduction pathways.Epidermal growth factor receptor(EGFR), one of human epidermal growth factor receptor(HER) family,has been the focus of anti-cancer research.To date, a variety of strategies to block HER signal have been developed.For eaxmple,monoclonal antibodies play a role in blocking the ligand binding to the extracellular region of HER receptors, tyrosine kinase inhibitors can inhibit HER receptors intracellular protein kinase activity.So far, several monoclonal antibodies (Cetuximab, trastuzumab) and tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib) have been marked, achieved the purpose of cancer treatment by blocking the HER signals.Erlotinib hydrochloride is a EGFR tyrosine kinaseinhibitor.Erlotinib monotherapy applys to locally advanced or metastatic Non-small cell lung cancer(NSCLC), who received at least one failing chemotherapy in the past.We used 2-amino-4,5-bis (2-methoxyethoxy)ethylbenzoate hydrochloride as the starting material, directly condensed to ring, chlorinated, generating erlotinib hydrochloride after reacting with meta-amino phenylacetylene and refined to get high purityerlotinib hydrochloride. This synthetic route achieved thefollowingadvantages: mild reaction conditions, high yield, environment friendly,less by-products,simple post-processing, easy for industrial production, and it doesn’t involve the first class reagents or reagents harmful to experimental operation personnel.This paper verified and optimized the syntheticprocess. Intermediates were confirmed by MS and 1H-NMR.Thepurityof erlotinib hydrochloride was determined by high performance liquid chromatography and the structure of erlotinibhydrochloride was confirmed by various technologies, including ultraviolet-visiblespectrophotometry (UV), infrared spectrophotometry(IR), nuclear magnetic resonance (NMR), high resolution mass spectrum(HRMS) and X-ray powderdiffraction(XRPD). Physicochemical properties of erlotinib hydrochloride were measured, including appearance, hygroscopic, loss on drying, melting point, dry conditions, HPLC purity.