Studies On The Synthesis Process And Impurities Of Gefitinib

Gefitinib,a highly selective inhibitor of epidermal growth factor receptor(EGFR)tyrosine kinase,was developed by AstraZeneca for the treatment of EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer(NSCLC),and locally advanced or metastatic NSCLC after failure of previous chemotherapy.Gefitinib shows potent therapeutic effect and good safety.While in China,we only have the exclusive products of Qilu pharmaceutical and foreign import products of Gefitinib,whose prices are high.Thus it is important to study the synthesis of Gefitinib.Referencing multiple documents,this thesis selected a synthetic route with good stability,high yield,safe and suitable for industrial production.Gefitinib was synthesized from 3,4-Dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate by chlorination,ammoniation,hydrolysis,condensation and purification.The detection methods for intermediates and product were also developed.In the synthesis of GF-2,the dosage of chlorinated reagent was reduced.After reaction,the solvent was distilled by decompression,and the residue was stirred by toluene.GF-2 was obtained by separation,and was used directly in the next step without purification and drying.This process avoided the decomposition of GF-2 and significantly improved the purity and the yield of GF-2.In the preparation of GF-3,we investigated the reaction time,and founded that GF-3 could be directly used in the next step of reaction without drying.This process reduced the energy consumption and decreased operation time.In the preparation of GF-4,sodium hydroxide was chosen as a hydrolysis reagent,which decreased the reaction time,improved the purity.In the preparation of crude product,the temperature,reaction time and the feeding mode of propyl chloride morpholine were studied,which reduced the residual raw materials,decreased the impurities and improved the purity.In the purification process,the product was turned into hydrochloride,then adjusting pH to get the product.The purity of Gefitinib could reach more than 99.5%.Finally,recrystallized with 95%ethanol,the purity of Gefitinib could reach 99.9%,The purity of the product is high,and the process is simple and repeatable.At the same time,in order to control the quality of the product,the impurities of each step were analyzed and studied,and the impurities were successfully made.The optimized process is more convenient and the yield is high.The whole process is relatively friendly to the environment and is suitable for industrial production.In addition,the structures of the product and the intermediates were confirmed by 1H NMR and 13C NMR.